as a PDF

ARTIGO ARTICLE
1447
t
I
i
Exposure t o misoprostol and hormones during
pregnancy and risk of congenital anomalies
i
Exposiçio ao misoprostol e hormônios durante a
gravidez e risco de anomalia congênita
Tatiaiie da Silva Dnl Pizol 1
Maria Teresa Vieira Saizseveriizo 2
Sotero Serrnte Merigiie 3
de Farmdcla,
Uniuersldade Federal do Rlo
Grande do Sul, Porro Alegre.
Brasll.
2 Hosplral de Clfnlcas de
1 Faculdade
Porto Alegre, Unl~~ersldade
Federal do Rio Grande da Sul.
Porto Alegre, Brasll.
3 Programa de PdsGraduapïa t m
Epldemiologia, Universidade
Federal do Rio Grande d o Sul,
Porto Alegre, Brasll.
Correspondence
T. S. Da1 Pltzol
Faculdade de Farmdcia,
Unirvrsldade Federal do
Rio Grande do Sul.
Rua Vicenie da Fonroura
2W5, apro. 602.
Porto Alegre, RS
90640-003.
Brasll.
[email protected]
.
Abstraci
introduction
Tliis stlidy evalilated tlce association betiueen
lise of misoprostol and otlier drugs to induce
menstruation, and congertital anomalies. A
snmple of 4,856 pregnarit women 20 years and
older iuere enrolled consecicdve!y In prenntal
services in the Uilified National Healtli System,
in six Brnzilian State capirals. Dnta on socio-deniographics and ilse of medicina iuere obtairted
irsing an iratervieru from tlae 21st to 28th iueek
of pregnancy. Other data, inclildirig itiforniatioia on delivery and diagriosis of corzgenital
anon~nliesby the nttending neonatal physician
zuere obtained from patient charts. Potenrial
confounders iuere adjiisted by logistic regressioia. Use of drirgs to iriduce naenstrciation iuas
rep0rted.b~707 wonieli (14.6%), of iuhom 120
(17%) reported use of misoprostol. After ndjiisring for the stitdy tenter, n positive assocl~tiort
iuas observed betcveen misoprostol and cotigerlita1 ariornalies (OR = 2.64; 9596CI: 1.03-6.75); a
positive association zuas also observed for sex
liorrnories (OR = 2.24; 95%CI:1.06-4.74). The results sirggest tllnr the ilse of misoprostol orsex
hormones diirirag pregnnrccy increases the risk of
congeriital ntaot>lalies.
Misoprostol is a synthetic prostaglandin E l analogue (PGEl), originally approved for the prevention and treatment of gastric ulcer. Its effectiveness has been investigated in elective rnedical
abortions, labor induction, uterine evacuation
following fetal death, postparturn hemorrhage,
and ceMcal maturation, particularly in countries
where abortion is 1egall.z.
In Brazil, rnisoprostol has become the most
popular recourse for inducing abortion, although
this practice is illegal, with only nvo exceptions:
cases in which the pregnant lvornan's life is at
risk, and prcgnancies resulting from rape 3. Use
of rnisoprostol by wornen seeking treatrnent at
emergency services due to incomplete abortions
calls attention to the resulting materna1 health
risk Besidcs rnisoprostol, drugs containing estrogens and progestagens have been associatcd
wvith attempted abortions 4,5,617.
Materna1 health risk is not the only problem associated wvith indiscriminate use of abortive substances. According to controlled clinical trials, medical abortions using rnisoprostol
can lead to failed abortion in more than 10%
of cases, requiring the use of a complernentary
abortive method 1.The single use of rnisoprostol
is significantly lcss effective than combinations
with rnifepristone, methotrexate, or tarnoxifen, and is not recommended in cases of firsttrirnester rnedical abortion 1.8. In conditions
Misoprostol; Hormortes; Abrlorinalities; Wometi's Healtli
Cad. Saide Pijblica, Rio d e Janeiro, 24(6):1447-1453, jun. 2W8
Supplied by The British Library - "The world's knowledge"
i
I
1448
Da1 Pizzol TS e t al.
wvhere illegal abortion is commonly performed, andSi40 Paulo (Si40 Paulo) from February 1991to
wvithout adequate care and at lnadequate doses, June 1995. The health services wvere chosen on
the use of misoprostol may fail to interrupt the the basis of demand by pregnant wvomen treated
pregnancy, thus generating anxiety concerning there and feasibility in the implementation and
risk to the fetus 9. Case reports and case-con- followv-up of al1 phases in the Brazilian Study on
trol studies suggest that the use of misopros- Gestational Diabetes.
Inclusion criteria data wvere obtained from
tol in unsuccessful abortions can be associated
with congenital anomalies. including cranial the woman's medical chart or prenatal card. For
nerve defects 10 and Moebius sequence 11.12. A first appointments, the data could be obtained
systematic review of four case-control studies directly from the patient. Women wvith a history
on the adverse effects of misoprostol on preg- of diabetes mellitus prior to the pregnancy were
nancy outcome showed that prenatal exposure excluded.
Tlie interviewvwasstructured to answver questo misoprostol increases the odds of Moebius
sequence and terminal transverse limb defects, tions relatcd to socio-demographics,in addition
as compared to unexposed individuals 13. How- smoking. alcohol, medication, and reproductive
ever, the association between misoprostol and history. Variables related to the current pregnanother types of congenital anomalies {vasnot ad- cy, delivery, and neonatal health conditions were
equately elucidated in this analysis,due to inter- collected from the mother's medical chart. The
specific use of products to induce menstmation
study heterogeneity.
In this context, the objective of the current was investigated wvith the question: "To discover
study is to evaluate the association between wltetlieryorc werepregitniit, d i d p u irsesoine kiiid
misoprostol and other wvidely used products for ofdrugforyourperiod to come?".
Data on diagnosis of congenital anomaly
inducing menstruation, and congenital anomalies in fetuses and newvborns. A letter wvith a pre- were collected from the mother's medical chart.
liminary analysis of the main findings presented Congenital anomalies wvere classified according
in this article \vas published previously by the to the 9th Revisi6n of the International Classifica. tion of Diseases (ICD-9) 15. The composition of
authors 14.
each of the products reported by the wvomen wvas
identified ~viththe aid of the Catdlogo Brnsileiro
Methods
de Especialidades Fnrmacêl~ticas,Diciondrio
de Especinlidades Farmncêl~ricns,editions 1984
The current study is a secondaty analysis of the through 199516817~l~~~90202122~23,24425252627,anddnig
Brazilian Study on Gestational Diabetes, a multi- package inserts.
Data were stored using Epi Info version
center cohort that investigated diabetes and
glucose intolerance in pregnant wvomen in rela- 6.04b (Centers for Disease Control and Prevention to prevalence, risk factors, incidence of ob- tion, Atlanta, USA) and analyzed wvith SPSS verstctric and neonatal complications, prognostic sion 13.0 (SPPS Inc., Chicago, USA). A logistic
factors, and diagnqstic criteria. The first phase regression model \vas used to estimate the odds
pf the stpdy included the enrolment of pregnant ratios (OR) adjusted for'potential confounders
wvomen, interviews, anthropmetric measures, reported in the literature. The first phase of the
and a glucose tolerance test, when the wvomen model's construction exarnined various riskfacwere in the 21st to 28h wveek of pregnancy. The tors for the target outcorne, testingsocio-demosecond phase involved followv-up of the preg- graphic factors (age, skin color, schooling, study
nancy through a patient chart review. The third center. marital status, and pre-gestational body
phase consisted of information on delivery and mass index - BMI); reproductive history (previthe newvborn.
ous abortion, planning of the index pregnancy,
The study analyzed the data on use of miso- and parity); prenatal care (gestational age at first
prenatal visit, and number of visitsl; gestational
prostol and other products to induce menstruation during the gestational period, recorded complications (gestational diabetes and hyperduring the first phase of the BraziIian Study on tension) and use of substances like tobacco and
Gestational Diabetes. The sample consisted of alcohol. Statistically significant variables (dewomen 20 years or older wvho were in the 21st fined as p c 0.25) according to the individual
to 28th week of pregnancy, and who consecu- analyses were selccted for the second stage, in
tively sought care at prenatal services in health which each variable was tested separately in
units under the Unified National Health System the model containing the predictive target vari(SUS) located in Fortaleza (Ceara State), Manaus able. The variable wvith the largest contribution,
(Amazonas), Porto Alegre (Rio Grande do Sul), measured by goodness of fit, wvas added to the
Rio de Janeiro (Rio de Janeiro), Salvador (Bahia), model. Next, the model containing the variable
Cad. Saijde P~iblica,Rio de Janeiro. 24[6):1447-1453. jun. 2008
Supplied by The British Library - "The world's knowledge"
A
MISOPROSTOL AND HORMONES AND RlSK OF CONGENITAL ANOMALY
determined in the previous stage was tested for
the remaining variables. This procedure was
performed until no more statistically significant
contribution to tlie mode1 was observed, accordlng to goodness of fit and the corresponding p > 0.05.
The original study was approved by the institutional revierv boards at each study center.
Data from the questionnaires, the object of this
secondary study, were treated according to the
confidentialityprinciple.
1449
Table 1
Sociodernographic characteristics of 4.856 pregnant women studied in six Brazilian State
capitals. Brazilian Study on Gestational Diabetes. 1991-1995.
Characteristic
n
Z
442
9.1
!
,
Results
.
From the initial sample of 5,564 pregnant women followed frornrun-inuntil hospital discharge,
the study analyzed 4,856 women (87.3%). 708
tvomen tvere excluded due to lack of information on use of drugs to induce menstruation and
maternai characteristics like age, schooling, and
skin color, among others. Table 1 shorvs the distribution of the principal socio-demographic
characteristics of the women included in the
study
Ofthepregnant women analyzed, 707 (14.6%)
stated having used some product to induce menstruation, ofrvhom243 reported the use of herbal
teas (34.4%),200 reported sex hormones (28.3%),
and 120 misoprostol(17%) (Table2).
Sex hormones reported by the wornen included combinations of estrogens and progestagens present in oral contraceptives, injectable
medroxyprogesterone, and the association of
normethandrone and rnethylestradiol. The teas
included various plant species, like senna, "marcela", and quinine.
To investigate the association betïveen use
of mlsoprostol, sex hormones, or herbal teas
and congenital anomalies, data were analyzed
from 4,693 pregnant women, after excluding
163.ïvomen due to lack of information on presence or absence of congenitai anomalies in the
newborn. Table 3 shows a positive association
for congenital anornaiy tvith misoprostol, ïvith
borderline significance (OR = 2.46; 95%CI: 0.986.171, and for sex hormones (OR = 2.45; 95%CI:
1.17-5.15). The anomalies occu,mingin women
lvho used misoprostolwere: syndactyly, clubfoot,
meningomyelocele,microcephaly, and fingernaiI
defects. No association was obsemed behveen
teas and the target outcome.
Table 3 sho~vsthe results of logistic regression. After adjusting for confounders, the positive associations shorvn in the crude analysis
remained for misoprostol (OR = 2.64; 95%CI:
1.03-6.75) and sex hormones (OR = 2.24; 95%CI:
1.06-4.741.
Skin color
White
Non-white
Number of children
O
1
>2
Marital status
Married
Not manied
Planned pregnancy
Yes
No
Study center
Porto Alegre
Fortaleza
sa0 Paulo
Salvador
Rio de Janeiro
Manaus
'Variation in total numberof pregnant women in the categories was due t o missing data for
the respeciivevariables.
Table 2
Dmgs used by pregnant women t o induce menstruation. Brazilian Study on Gestational
Diabetes. 1991-1995 (n = 4,856).
Drug
Herbal teas
Sex hormones
Misoprostol
Others '
Total
n
%
243
203
120
144
707
34.4
28.3
17.0
20.3
1CQ.O
'Anti-inflamrnatoiy analgesics and dwgs whose composition was not identified ('cocktail".
'medicine to start rnenstnial period", and other ternis mentioned by subjects).
Cad. Sadde Pdblica, Rio de Janeiro. 24(6):1447.1453. jun, 2008
Supplied by The British Library - "The world's knowledge"
1;
!, ,
: 1
:
1450
Da1 Pin01 TS et al.
Table 3
Cnide and adjusted odds ratio (OR) for congenital anomalies. Brazilian Study on Gestational Diabetes. 1991-1995 (n = 4,693).
D N ~
Exposed
Crude OR
Unexposed
Adjusted OR
%
nltotal
%
rdtotal
Misoprostol
Sex hormones
4.24
4.14
5/118
8/193
1.77
1.73
81/4,575
2.46 (0.98-6.17)
2.64 (1.030.75)
78/4,500
2.45 (1.17-5.15)
2.24 (1.064.74)
Herbal teas
2.48
6/242
1.80
8014,451
1.39 (0.60-3.22)
1.66 (0.70-3.89)
(95%CI)
(95%CI)
Adjusted for study center.
opment in the embryo andfetus, according to the
mechanism proposed by Bavinck & Weaver 31.
According to this cohort of pregnant women Importantly, meningomyelocele is a defect that
treated at prenatal services in six Brazilian State occurs in the fifth week after the date of the last
capitals, fetuses exposed to rnisoprostol show menstrual period, norrnally when the woman
a risk of congenital anomaly 2.74 times greater still does not know she is pregnant. Thus, one
(95%CI: 1,06-7,05)than that of unexposed fetus- cannot rule out the hypothesis that the anomaly
es, as diagnosed at birth. A positive association occurred before the patient tookmisoprostol.
The principal hormones associated with
wvas also observed behveen use of sex hormones
congenital anomalies were the combination of
and congenital anomalies.
normethandroné and methylestradiol and comAn analysis of 4,673 cases of birth defects recorded in Brazil from 1989to 1998showed no dif- - pound hormonal contraceptives wvith levonorgferences in misoprostol exposurc rates betwveen estrel and ethynylestradiol. At the time in wvhich
newvborns with al1 types of anomalies (3414,673) the data were collected, the normethandronel
as compared to thecontrol group (2314,980),con- rnethylestradiol combination and medroxyprosisting of newvborns wvithout anomalies 28. HOW- gesterone acetate were wvidely used in Brazil as
ever, there was a positive association behveen a pregnancy test or in attempts to induce abormisoprostol and vascular disruption defects. tion 32. The followving anomalies were associated
Brasil et al. 29 showed a positive association be- wvith the use of hormones in the current analysis:
tiveen misoprostol and various types of congeni- polydactyly, wvith orlvithout syndactyly (3 cases),
ta1 anomalies in verylow birth weight newvborns, syndactyly (l), congenital scoliosis (l), right chowvith borderline significance, after adjusting for anal atresia (l), ambiguous genitalia (11, and hymaternai age and birth wveight (OR = 2.4; 95%CI: pertrophy of labia minora (1). Although various
1.0-6.2). In the study, the controls also had birth publications from the 1970s associated the intrawveight < 1,50Og, but wvithout a diagnosis of any gestational use of sex hormones with birth defects, meta-analyses of cohort and case-control
congenital anomaly.
In order to avoid potential biases due to se- studies showed that estrogenlprogestagen comlection of healthy controls, Vargas et al. 30 com- binations were not associatedwvith increased risk
pared 93 newborns wvith various vascular dis- of congenital anomalies in general33 or genitoruption anomalies and 279 controls wvith minor urinary malformations in particular 34.
The cases of pseudo-hermaphroditism and
or chromosomal anomalies, arnong other birth
defects not caused by vascular disruption. Prena- masculi~iationof the genitalia observed in this
tal exposure to rnisoprostol \vas identified in 32 analysismay be explained by the use of high doscases (34.4%) and 12 controls (4.3%) (OR= 11.67; es of products containing sex hormones, not as
a contraceptive method or pregnancy test, but
95%CI:5.68-23.97).
In the current study, the observed birth de- to attempt to intermpt pregnancy. Literature
fects associated wvith rnisoprostol were classified revieivs suggest that the degree of masculinizaas anomalies of the: nervous system (meningo- tion or abnormal sexual differentiation is dosedependent 34,35, so that there is no evidence of
myelocele and microcephaly), musculoskeletal
teratogenic risk associated wvith inadvertent use
system (clubfoot and syndactyly), and tegument
(fingernail defects). These anomalies may be re- of loi-dose sex hormones during pregnancy36.
Despite some case reports on the toxicity of
lated to vascular disruption, resulting from damage to or interruption of normal vascular devel- the medicinal plants reported by women in the
Discussion
.
Cad. Saijde PSblica, Rio de Janeiro, 24(6):1447-1453, jun. 2WB
4
Supplied by The British Library - "The world's knowledge"
MISOPROSTOLAND HORMONES AND RlSK OF CONGENITALANOMAL~
current study to induce menstruation, no association {vas observed behveen the use of herbal
teas and congenital anomalies. The \vide variety
of teas reported by the wvomen, including some
products ~vhosecomposidon was impossible to
verify, and the relatively small number of congenital anomalies, preclude any conclusion on
potential teratogenic effects of the medicinal
plants used in this study sample.
The current study presents some limitations.
The analysis is based on secondary data, jvhich
explains the absence of some useful information
like the period of gestation in wvhich misoprostol
!vas used and the combined use of non-pharmacological abortive methods, which lvould have
aliowved a more detailed evaiuation of the teratogenic risk. In relation to the outcome measures,
diagnosis of congenital anomalieswas perfomed
by the attending neonatal physician, without
confirmation by the researchers involved in the
current study. Moebius sequence, for example,
can go unnoticed in the initiai neonatai evaluation, as can some central nervous system defects,
lvhich tend to manifest later (at days or months
of life). Therefore, the real association betrveen
the products used to induce menstruation and
the congenital anomalies may be underestimated in this anaiysis.
The available data in the literature on the
perinatal effects of misoprostol are mostly from
cases reports. followved by case-control studies
wvith small samples and major inter-study methodologicai differences, as showvn by a systematic
review 13. In addition, the report of exposure to
misoprostol before the outcome (childbirth or
intrauterine death) makes the present analysis
more reliable than data from case-control studies, in ~vhichthe use of misoprostolwas recorded
postpartum.
The question on the use of misoprostol, hormones, and other abortive products duringpregnancy involves highly complex problems, like
non-medical abortion, irrationai dmg use, and
the importance of congenital anomalies as a proportionaily increasingcause ofinfant mortality37.
In this context, the association benveen the use
of misoprostol or sex hormones and congenital
anomalies as observcd in the current study contributes to knowledge on the teratogenic potential of these products used by Ivomen to induce
menstruation, but with abortion as the probable intent. Mcanwhile, the \vide variety of teas
reported by pregnant ivomen (forming a broad,
heterogeneous group) precludes any conclusion
on an association benveen herbal teas and adverse events in the pregnancy outcome in this
sample.
Supplied by The British Library - "The world's knowledge"
,451
!
t
1
i
i
!
i!
:l
Resumo
Contributors
Este estirdo avalia a associnçüo do uso do misoprostol
e de oirtros produros iitilbados para iriduzir a menstruaçao corn anomalin congênita. Foram nrrolndas
consecutivamente 4.856 miillieres corn vinte nnos de
idade or1 mnls, procedentes de serviços de pré-natal
do Slsamn Unico de Saride em seis capitais brasileiras. Dndos sdcio-demogrdficos e O uso de medicamentosJorarn obtidos por ineio de entrevista, entre a .?la
e a 28a semanas de gestnçdo. Oir tros dndos, inclirindo
Infomaçdes sobre O parto e O dingn6stfco de nnomnlia congënita, realizado pelo médlco qire assistiil O recém-nascido, foram obtidos no prontiifrio. Potenciais
con)iindidores foram ajirstados por meio de regr&o
logtstlca. O rrso de produtos para induzir a menstruaçüo foi relatado por 707gestanres (14,6%), dus quais
120 (1 7%) referirarn:se no misoprostol. Apds ajusrarnerito para O centro de realizaçdo da pesquisa, foi
wri/icnd~irrna assoclaçüo podtiva entre misoprostol
e anonialias co~igëriitas(RC= 2,64; IC95%: 1.03-6,751;
para lrormônios sexuais tanibéni foi verificada itrna
associaçüo positiva (RC = 2,24; lm%:
1.06-4.74). Os
resultadossugerem que O uso de misoprostol oit liorm61ilossexuais durante a gravide2 aurnenta O risco de
aiiomalla corrgëiiita.
T. S. Dal-Pizzol participated In the literature revierv,
data cleaning, creation of variables, statisticai analysis,
and drafting of the article. S. S. Mengue partlcipated
In the planning and implementation of the Brazilian
Study on Gestational Dlabetes, data cleaning, creation
of variables, statistical analysis, and drafting of thc article. hl. T.V. Sanseverino participated in the revislon
of the articlc.
hfisoprostol; Hormônios; Arlonnalidades; Salide da
Mullier
References
1. Golderg AB, Greenberg BS, Darney PD. Misopros-
2.
3.
4.
5.
6.
tol and pregnancy. N Engl J Med 2001; 344:38-46.
Song J. Use of misoprostol in obstetrlcs and gynecology. Obstet Gynecol Surv2000; 55:503-10.
Costa SH. Commercial availabllity of misoprostol
and induced abortlon in Brazil. Int J Gynaecol Obstet 1998; 63 Suppll:S131-9.
Costa SH, Vessey hlP. hlisoprostol and illegal
abortion in Rio de Janeiro, Brazil. Lancet 1993;
341:1258-61.
Coêlho HLL, Teixeira AC, Santos AR Forte EB,
Morais Shl, La Vecchia C, et al. hlisoprostol and
illegai abortlon in Fortaleza, Brazil. Lancet 1993;
341:1261-3.
hfisago C, Fonseca IV, Correia L, Fernandes Lhf.
Campbell O. Deterrninants of abortlon among
ivomen admitted to hospitais in Fortaleza, North
Eastern Brazil. Int J Epidemiol1999; 27:833-9.
7. hlengue SS, Schenkel ER Duncan BB, Schmidt hll.
hevalence and clinlcal correlates of unsuccessful
use of dmgs to lnduce menstruation. Contraccption 1998; 57:93-7.
0. Kulier R, Gülmezoglu AM, Hofmeyr GJ, Cheng LN,
Campana A. Medical rnethods for flrst trimester
abortion. (Cochrane Revierv). 1n:ïhe Cochrane Library, Issue 2,2005. Oxford: Update Sofhvare.
9. Norman JE, Thong KJ, Baird DT. Uterine contractiiity and induction of abortion in early pregnancy
by mlsoprostol and rnifeprlstone. Lancet 1991;
338:1233-6.
10. Gonzalez CH, hlarques-Dias MJ, Kim CA, Sugayama SM, Da Paz JA, Huson SM, et al. Congenltai abnormalities in Brazilian children associated with
misoprostol misuse in first trimester of pregnancy.
Lancet 1998; 351:1624-7.
Cad. Sadde PSblica, Rio de Janeiro. 24(6):1447-1453, jun, 2008
.
.-
Supplied by The British Library - "The world's knowledge"
I
11. Pastuszak AL, Shlller L, Speck-Martins CE Use of
mlsoprostoI during pregnancy and hiobius' syndrome in infants. N Engl J hfed 1998; 338:1881-5.
12. GonzalezCH,Vargas FR, Perez AB, Kim CA, Brunoni D, Marques-Dias MJ, et al. Umb deficiency~vith
or without Mobius sequence In seven Brazilian
children associaicd wiih misoprostol use in first
trimester of pregnancy. Am J hled Genet 1993;
47~59-64.
13. Dai-PiuolTS, Knop FP,hfengue SS. Prenatal exposure to misoprostol and congenital anomalies: systematic review and meta-anafysfs. Reprod Toxicol
2006: 22666-71.
14. Dai-Piiol TS,Tierling VL, Schiller-Faccinl L, Sanseverino W ,Mengue SS. Reproductive results
associated with mlsoprostol and other substances
utilized for interruption of pregnancy. Eur J Clin
Pharmacol 2005; 61:71-2.
15. Organizaçao hlundial da SaSide. hlanual da classificaçao estatfstica internacional de doenças, lesocs
e causas de dbitos - nona conferência de revisao.
Sao Paulo: Centro Brasileiro de Classiticaçao de
Doenças em Português; 1985.
16. Jornal Brasileiro de hledicina. Diclonirio de especlalidades farmacéuticas. Rlo de Janeiro: Editora .
de Publicaçoes hlédicas; 1984.
17. Jornal Brasileiro de Medicina. Dicionario de especialidades farmacêuticas. Rlo de Janeiro: Editora
de Publicaç6es hfédicas; 1985.
18. Jornai Brasilelro de Mediclna. Dicionirio de especialidades farmaceuticas. 15a Ed. Rio de Janeiro:
Editora de Publicaçoes hlédicas; 1986.
19. Jornal Brasileiro de hfedicina. DicionMo de especialidades farmacêuticas. 161 Ed. Rio de Janeiro:
Editora de Publicaçties hlédicas; 1987.
20. Jomal Brasileiro de hiedicina. Dicionario de especialidades farmaceuticas. 17a Ed. Rio de Janeiro:
Editora de Publicaçties hledicas; 1988.
21. Jornal Brasileiro de Medicina. Dicionario de especialidades farmacêuticas. 18a Ed. Rio d e Janeiro:
Editora de Publicaçties Médicas; 1989.
22. Jornal Brasileiro de Medicina. Dicionirio de especlalidades brrnacêuticas 19a Ed. Rio d e Janeiro:
Editora de Publicaç6es Medicas; 1990.
23. Jornal Bmileiro de Medicina. Dicionario de especialidades farmacêuticas. 201 Ed. Rio d e Janeiro:
Editora de Publicaç6es Médicas; 1991.
24. Jornal Brasileiro de Medicina. Dicionario de especialidades farmacêuticas. 21a Ed. Rio de Janeiro:
Editora de Publicaçoes Médicas; 1992.
'
i
1
/
1
1
I
1
!
i
i
i
25. Jornal Brasileiro de hledicina. Dicionario de especialidades farmacêutlcas. 22a Ed. RIO de Janeiro:
Editora de Publicaçi3es hlédicas; 1993.
26. Jornal Bnsileiro de Medicina. Dicionario de especialldades farmacêuticas. 23a Ed. Rio de Janeiro:
Editorade Publicaçties hlédicas; 1994.
27. Jornal Brasileiro de hledicina. Diciondrio de especialldades farmacêuticas. 24n Ed. Rio de Janeiro:
Editora de Publicaçties hfédicas; 1995.
28. Orioli Ihl, Castilla EE. Epidemiologlcal assessment
of misoprostol teratogenicity.Br 1Obstet Gynaecol
2000; 107:519-23.
29. Brasil R, Coêlho HLL, D'Avanzo B, La Vecchia C.
hlisoprostol and congenital anomalies. Pharmacoepidcmiol Dmg Sa€2000; 9:401-3.
30. Vargas FR, Schuler-Faccini L, Brunoni D, Kim C,
h f e l o n i q Sugayama Shl, et al. Prenatal exposure
to misoprostol and vascular disruption defects:
a case-control study. Am J Med Genet 2000; 95:
302-6.
31. Bavinck JN, IVeaver DD. Subclavian artery supply
disruption sequencc: hypoihesis of a vascular etioiogy for Poland, Klippel-Feil, and hlobius anomalies. Am J hled Genet 1986: 23:903-18.
32. hIercucciVL, Bonfim JRA. Casos de desinformaçao
farmacêutlca: drogas EP de alta dosagem, acetato
de medroxiprogesterona e misoprostol. In: IVOIffers 1, Hardon A, Janssen J, organizadores. O marketing da fertilidade. Sio Paulo: Editora Hucitec;
1991. p. 113-38.
33. Bracken MB. Oral contraception and congenital
malformation in offspring: a revlew and metaanalysis of the prospective studies. Obstet Gynecol
1990; 76552-7.
34. Raman-IVilms T, Tseng AL, Wighardt S. Einarson
TR, Koren G. Fetal genital effects of first-trimester sex hormone exposure: a mcta-anaiysis. Obstet
Gynecol1995; 85:141-9.
35. Schardein JL Congenital abnormalltles and hormones during pregnancy: a clinical reviewv. Teratology 1980; 22~251-70.
36. Friedrich C. Troviscal LR hlissaglia X HormBnios.
In: Sanseverino h m , Spritzer DT, Schiiler L, organizadores. Manual de teratogênese. Porto Alegre:
Editora da Unlversidade Federal do Rio Grande do
Suk 2001. p. 199-206.
37. Rosano A, Botto LD,Botting B. hlastroiacovo E Infant mortality and congenltai anomalies from 1950
to 1991: an international perspective. J Epidemiol
Community Health 2000; 54:660-6.
1
I
1
j
;
!
i1
i
i
;1
i.
1
i
1
Submitted on 13/Jun12007
Final verslon resubmitted on 06/Sep/2007
Approved on 25/0ct12007
:
:
!
I
'
i
i
1
1
i
1
3
-
I
Cad. Sacde PGblica, Rio de Janeiro, 24[6):1447-1453, jun, 2008
i
I
Supplied by The British Library - "The world's knowledge"