Download 妊娠甲亢药物治疗的先天性畸形风险的Meta分析 李翔，刘皈阳，马建丽

妊娠甲亢药物治疗的先天性畸形风险的 Meta 分析
李翔，刘皈阳，马建丽，周亮（解放军总医院第一附属医院药剂药理科 北京 100048）
摘要：目的 评估使用丙硫氧嘧啶或甲巯咪唑治疗妊娠甲亢与先天性畸形的关联。数据来源 通
过搜索 Medline，Pubmed，Cochrane Library 和 EMBASE。研究选择 因无随机对照试验，故
选择队列研究和病例对照研究进行 Meta 分析。合成 7 个研究被纳入 Meta 分析。与对照组（OR
1.76，95% CI 1.47-2.10）和未用药组（OR 1.71，95% CI 1.39-2.10）比较，使用甲硫咪唑的妊
娠甲亢孕妇的出生缺陷风险是增加的。在甲巯咪唑和丙硫氧嘧啶之间转换会增加出生缺陷的
比值比（OR1.88，95% CI 1.27-2.77）。与未用药组比较，使用丙硫氧嘧啶治疗妊娠甲亢的风
险相当（OR 1.18, 95% CI 0.97-1.42）。与健康对照组比较（OR 1.29，95% CI 1.07-1.55），丙
硫氧嘧啶只稍微增加了先天性畸形的风险。接受甲巯咪唑治疗的妇女比丙硫氧嘧啶治疗对胎
儿的风险是增加的。结论 根据出生缺陷的风险可以发现丙硫氧嘧啶治疗妊娠甲亢是一个较为
安全的选择，甲硫咪唑和丙硫氧嘧啶之间的药物转换并不能降低胎儿的出生缺陷。
关键词：甲状腺机能亢进、先天性异常、丙硫氧嘧啶、甲硫咪唑、怀孕、Meta 分析
李翔，[email protected]，13717533608
Risk of congenital anomalies with antithyroid treatment during pregnancy: A meta-analysis
Xiang Li, Gui-Yang Liu, Jian-Li Ma, Liang Zhou
Department of Pharmacy, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing,
China
ABSTRACT
OBJECTIVE: To evaluate the association of either propylthiouracil or methimazole with
congenital malformations for the treatment of hyperthyroidism during pregnancy.
DATA SOURCES: Relevant studies were identified by searching Medline, Pub Med, Cochrane
Library and EMBASE.
STUDY SELECTION: We intended to include randomized controlled trials, while no trials were
located. Thus we had to include cohort studies and case-control studies for this meta-analysis.
SYNTHESIS: A total of 7 studies were included for meta-analyses. In the meta-analyses, increased
risk of birth defects was found among pregnant women with hyperthyroidism treated with
methimazole when compared to that in control group (Odds ratio 1.76, 95% Confidence interval
1.47-2.10) or in non-exposure group (Odds ratio 1.71, 95% Confidence interval 1.39-2.10).Maternal
shift between methimazole and propylthiouracil were associated with an increased odds ratio of
birth defects (Odds ratio 1.88, 95% Confidence interval 1.27-2.77). Equal risk of birth defects was
found among pregnant women with hyperthyroidism treated with propylthiouracil when compared
to that in non-exposure group (Odds ratio 1.18, 95% Confidence interval 0.97-1.42). There was just
a slight trend towards an increased risk of congenital malformations in infants whose mother were
treated with propylthiouracil when compared with healthy controls (Odds ratio 1.29, 95%
Confidence interval 1.07-1.55). Children of women receiving methimazole treatment had increased
risk of adverse fetal outcomes relative to mothers receiving propylthiouracil treatment.
CONCLUSION: We found propylthiouracil was a safer choice in treating pregnant women with
hyperthyroidism according to the risk of birth defects, and a shift between methimazole and
propylthiouracil failed to provide protection against birth defects.
KEYWORDS: hyperthyroidism, congenital anomalies, propylthiouracil, methimazole, pregnancy,
meta-analysis
INTRODUCTION
Hyperthyroidism during pregnancy is uncommon and affects about 1 in 500 pregnancies (1).
Overt hyperthyroidism has well-documented adverse impacts on pregnancy outcomes, such as
preterm birth, congenital anomalies, pre-eclampsia and so on (2-4). Therefore, despite its rarity,
proper management of hyperthyroidism during pregnancy is of utmost importance. Medical therapy
is preferred by most authorities, as radioiodine is contra-indicated and thyroidectomy requires
pre-treatment with antithyroid drugs and may be complicated by surgical adverse effects (5). The
available antithyroid drugs (ATD) are propylthiouracil (PTU) and methimazole (MMI)/carbimazole
(CZ). They are equivalent in terms of their efficacy in the treatment of clinical hyperthyroidism (6).
As for hyperthyroidism during pregnancy, some reports suggest an association between a specific
congenital malformation (MMI embryopathy) and prenatal exposure to MMI (7). A specific
malformation pattern related to prenatal MMI exposure consists of choanal and esophageal atresia,
scalp defects, minor facial anomalies and psychomotor delay (8). The reported facial anomalies
usually include upward slanted palpebral fissures, arched flared eyebrows and small nose with a
broad bridge (9). Recently, a study conducted by Anderson et al demonstrated that ventricular septal
defect (VSD) is also the part of MMI embryopathy (10). Compared with non-exposed children, the
use of MMI/CMZ in early pregnancy (up to and including gestational week 10) is associated with
an increased risk of VSD. PTU may be safer than MMI and should be considered as the first-line
agent in the treatment of hyperthyroidism during pregnancy (11). In contrast, other studies found
equal risk of birth defects among pregnant women with hyperthyroidism treated with PTU and with
MMI (12). Furthermore, a number of major birth defects in the offspring of women treated with
PTU were also observed (13). Unilateral kidney agenesis, malformations of the face and neck
region were associated with in utero exposure to PTU. In a case-control study conducted by
Clementi et al, PTU exposure was associated with a significantly increased risk of situs inversus
with or without dextrocardia (6). Recent animal studies demonstrated that PTU is teratogenic during
late blastula, gastrulation and neurulation. It could alter ciliary-driven flow and disrupt the normal
genetic program involved in left right axis determination (14). Thus there is no consensus regarding
the best method of therapy for hyperthyroidism during pregnancy. In this paper, we evaluated the
association of either PTU or MMI with congenital malformations for the treatment of
hyperthyroidism during pregnancy and conducted a systematic review.
METHODS
Literature search and study selection
Relevant studies were identified by searching Medline, Pub med, Cochrane Library and
EMBASE published until July 2014. Search criteria used were related to thyroid function and
pregnancy outcome. Specifically the following search items were used: thyroid*，hyperthyr*,
Graves disease, PTU, propylthiouracil, MMI, methimazol, congenital malformation, birth defect,
congenital anomalies. There were no language limitations for the initial search. Randomized
Controlled Trials (RCTs), cohort studies and case-control studies were included. Data on the effect
of combinational therapy were excluded.
Data extraction
Titles and abstracts of the articles were screened by two reviewers (X Li and L Zhou)
independently. Included articles for full text screening were compared during a consensus meeting.
In case of disagreement, a third reviewer (JL Ma) was consulted for the decision on inclusion or
exclusion for full-text evaluation. Articles that did not contribute to the answer of our research
questions after full text evaluation were excluded. Hyperthyroidism was defined as low TSH with
high free T4. After consensus the remaining articles were included for critical appraisal and
assessed by two reviewers independently. Articles (RCT studies) were judged on scientific quality
according to the CONSORT and STROBE statement (15,16).
Data analysis and statistical methods
The significance of the combined odds ratio (OR) was determined by the Z-test, in which
P<0.05 was considered significant. The χ2-based Q statistical test was used for the assessment of the
between-study heterogeneity, which was considered significant for P<0.1. In analyses, if the
heterogeneity was low, then we used a fixed-effect model, or else applied the random-effect model.
Software of Review Manager 5.3 was used to perform the meta-analyses (available from Cochrane).
RESULTS
Figure 1 shows the selective process after the search: Of the 7 included articles in this
systematic review, 6 reported on MMI use, 6 reported on PTU use and 2 reported on shifts in MMI
and PTU. Patients in the included studies were pregnant women with hyperthyroidism, who needed
the anti-thyroid medication treatment to maintain thyroid hormone levels within the normal range.
Controls were all pregnant women, either euthyroid or were hyperthyroid but were seen late in
pregnancy; the latter patients were delivered before therapy and didn’t need any anti-thyroid
medication therapy (12).
Figure 1. Flow chart of literature search and article selection.
Characteristics of the studies
The characteristics of the included articles are reported in Table 1.
The effect of PTU use on congenital malformations
A total of 7 studies reported on congenital malformations after exposure to PTU. When
compared with healthy pregnant women, only one study showed an increased risk for congenital
malformations in pregnant women treated with PTU (17). Another three studies didn’t show any
difference in congenital malformation rate (13, 18, 19). Meta-analysis of these four studies on
exposure to PTU and congenital malformations resulted in a pooled OR of 1.29, 95% CI 1.07-1.55,
indicating a mild difference (Figure 2A). We further compared the risk of congenital malformations
in pregnant women exposure to PTU with that in women without ATD use during pregnancy. The
pregnant women without ATD use were either euthyroid throughout pregnancy and required no
medications or were hyperthyroid but were seen late in pregnancy. The latter patients were
delivered before therapy. There were no statistically significant differences between exposure to
PTU and risk of birth defects: a pooled OR of 1.18, 95% CI 0.97-1.42 (Figure 2B).
Figure 2. Forest plot of Odds Ratio's and 95% Confidence Interval of pooled studies. (A)
Comparing PTU-treated pregnant hyperthyroid women with healthy pregnant ones according to risk
of congenital anomalies. (B) Comparing PTU-treated pregnant hyperthyroid women with pregnant
hyperthyroid ones without antithyroid drug treatment according to risk of congenital anomalies.
The effect of MMI use on congenital malformations
As shown in Figure 3A, six studies reported on congenital malformations after exposure to
MMI. Three studies showed an increased risk for congenital malformations in pregnant women
treated with MMI when compared to that in control group (11, 17, 20). Another three studies didn’t
show any difference in congenital malformation rate (12, 13, 18). Meta-analysis of these six studies
on exposure to MMI and congenital malformations resulted in a pooled OR of 1.76, 95% CI
1.47-2.10, indicating significant difference. Even compared with women without ATD use during
pregnancy, there was also a significantly increased risk of birth defects in women exposure to MMI:
a pooled OR of 1.71, 95% CI 1.39-2.10 (Figure 3B).
Figure 3. Forest plot of Odds Ratio's and 95% Confidence Interval of pooled studies. (A)
Comparing MMI-treated pregnant hyperthyroid women with healthy pregnant ones according to
risk of congenital anomalies. (B) Comparing MMI-treated pregnant hyperthyroid women with
pregnant hyperthyroid ones without antithyroid drug treatment according to risk of congenital
anomalies.
The effect of shifts in MMI and PTU use on congenital malformations
As shown in Figure 4, two studies reported on congenital malformations after swifts in MMI
and PTU. Both studies showed an increased risk for congenital malformations in pregnant women
treated with shifts in MMI and PTU when compared to that in control group (13, 17). Meta-analysis
of these two studies resulted in a pooled OR of 1.88, 95% CI 1.27-2.77, indicating significant
difference.
Figure 4. Forest plot of Odds Ratio's and 95% Confidence Interval of pooled studies comparing
pregnant hyperthyroid women with a shift between PTU and MMI with pregnant hyperthyroid ones
without antithyroid drug treatment according to risk of congenital anomalies.
The effect of antithyroid drugs on congenital malformations
As shown in Figure 5, five studies reported on congenital malformations after exposure to PTU
or MMI. Meta-analysis of these five studies resulted in a pooled OR of 0.73, 95% CI 0.56-0.96,
indicating PTU was a safer choice according to risk of birth defects in pregnant women with
hyperthyroidism.
Figure 5. Forest plot of Odds Ratio's and 95% Confidence Interval of pooled studies comparing
PTU-treated pregnant hyperthyroid women with MMI-treated ones according to risk of congenital
anomalies.
DISCUSSION
A number of studies have linked hyperthyroidism during pregnancy with an increased risk of
congenital anomalies. However evidence regarding the impact of antithyroid drugs, such as PTU
and MMI on pregnancy outcomes remains controversial. The preferred antithyroid drug during
pregnancy in the USA is PTU and in Europe is MMI (21, 22).
In this study, we compared the risk of congenital anomalies among pregnant woman with
hyperthyroidism classified into three groups: receiving PTU treatment, receiving MMI treatment,
and receiving PTU or MMI first and then swift to MMI or PTU respectively. In addition, we also
enrolled two control groups in this study: completely healthy pregnant women and hyperthyroid
women without ATD exposure. Usually severe hyperthyroidism during pregnancy can cause
various complications for both the mother and the fetus (23). Thus the pregnant women without
ATD use were either euthyroid throughout pregnancy or were hyperthyroid but were seen late in
pregnancy. The latter patients were delivered before therapy.
When compared with hyperthyroid women without ATD use or healthy pregnant controls, the
most significant increase in the rate of major anomalies was in the MMI treatment group. There was
just a slight trend towards an increased risk of congenital malformations in infants whose mother
were treated with PTU when compared with healthy controls. The risk of birth defects for
hyperthyroid women treated with PTU and women without ATD use were similar. Since women in
the non-exposure group were almost the healthy ones, the similar rate between the two groups
above indicated that PTU was a preferred option according to the risk of congenital anomalies.
However, there was a limitation to the studies. It was confounding between the hyperthyroidism
itself and the drug effect in producing the adverse fetal outcomes. It was reasonable to expect that
the more severe examples of hyperthyroidism were the very women for whom drug treatment was
likely to be prescribed, particularly in higher doses. Hence the adverse fetal outcome could be the
result of the underlying severe hyperthyroidism or of the treatment. To adjust for the confounding
factors, we considered that the eligible subjects for this study were pregnant women with
hyperthyroidism who received ATD treatment. Then we compared PTU use with MMI use in the
overall rate of anomalies; our data supported the use of PTU as well. Taken together, these results
indicated that PTU was a safer choice in the treatment of pregnant women with hyperthyroidism
according to the risk of birth defects. This is in accord with an American Thyroid Association
statement for use of PTU as the first-line agent in the management of hyperthyroidism during
pregnancy (24).
Recently a systematic review conducted by Hackmon et al described the safety of MMI and
PTU in pregnancy as well (25). They concluded that MMI is a teratogen, which was consistent with
our studies. In most cases associated with MMI-embryopathy in the case reports they reviewed, the
exposure to MMI did indeed occur in the first trimester during the critical embryogenic period. In
our research, among 6 studies comparing the MMI exposure and the risk of birth defects, a total of 3
studies (Anderson et al, Yoshihara et al, and Momotani et al) reported on the risk of congenital
anomalies after intrauterine exposure in the first trimester. Their findings showed that MMI
treatment significantly increased the risk of congenital malformations. The remaining studies (Chen
et al, Korelitz et al, Wing et al), which didn’t describe whether the ATD treatment was in the first
trimester, failed to confirm a causal relationship between MMI and malformations. It was probably
due to the exposure beyond the period of organogenesis.
Shifts in PTU and MMI were not common in the treatment of patients with hyperthyroidism.
Two included articles didn’t explain the reason why the doctors preferred this treatment. It was
probably related to potential concerns about MMI teratogenic effects in the first trimester and a
PTU hepatotoxicity during pregnancy (26, 27). Thus it was suggested that for pregnant women,
PTU use be restricted to the first trimester, and MMI be used in the remainder of pregnancy to
minimize potential risks to the fetus and mother. Our study illustrated that shifts between MMI and
PTU may give little protection against birth defects. This conclusion was inconsistent with previous
study conducted by Hackmon et al. They demonstrated that PTU should be administered during the
first trimester and switched to MMI for the remainder of the pregnancy. One possible explanation
for the disagreement might be as follows: due to severe PTU-induced hepatotoxity, women with
hyperthyroidism might be treated with MMI. The swift from MMI to PTU may occur when they
found they were pregnant. It was highly possible that exposure to MMI was during the critical
embryogenic period (4 to 10 weeks) since under most circumstances, women had actually been
pregnant for more than one month when they found they were pregnant. For instance, one study in
our research described that the mean time from pregnancy start to the shift to PTU treatment was 44
days. In addition, considering shifts in PTU and MMI, there were two types of drug prescribing
patterns in the involved studies: from PTU to MMI and from MMI to PTU. We should examine
whether the prevalence of birth defects differed according to types of ATD drug prescribing
patterns.
However, there was no evidence from current trials to guide a choice between PTU and then
switching to MMI or MMI and then switching to PTU. So it was certain that changes in antithyroid
drug prescribing patterns would not be necessary during pregnancy. In order to avert shifts in ATD
use, it was recommended that women of child-bearing age should choose PTU therapy before
pregnancy to minimize the potential risk of congenital malformations.
LIMITATIONS
Our research provided important population-based estimates of medication use that are
relevant to the care of pregnant women with hyperthyroidism. However definite answer to this
question remained unclear since there are no randomized controlled trials comparing antithyroid
treatments in pregnant women with hyperthyroidism up to now. More human epidemiology studies
were needed and new evidence-based recommendations should be developed for the treatment in
women with hyperthyroidism during pregnancy.
CONCLUSION
Despite no RCT studies, we think that our study offers potentially useful data that might be of
value to physicians prescribing anti-thyroid drugs for pregnant women with hyperthyroidism. The
limited evidence shows PTU was a safer choice in treating pregnant women with hyperthyroidism
according to the risk of birth defects, and a shift between MMI and PTU failed to provide protection
against birth defects.
REFERENCES
1. Mestman JH. Hyperthyroidism in pregnancy. Curr Opin Endocrinol Diabetes Obes. 2012; 19(5):
394-401.
2. Inoue M, Arata N, Koren G, Ito S. Hyperthyroidism during pregnancy. Can Fam Physician. 2009;
55(7): 701-3.
3. Vissenberg R, van den Boogaard E, van Wely M, van der Post JA, Fliers E, Bisschop PH, et al.
Treatment of thyroid disorders before conception and in early pregnancy: a systematic review.
Hum Reprod Update. 2012; 18(4): 360-73.
4. van den Boogaard E, Vissenberg R, Land JA, van Wely M, van der Post JA, Goddijn M, et al.
Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception
and in early pregnancy: a systematic review. Hum Reprod Update. 2011; 17(5): 605-19.
5. Azizi F, Amouzegar A. Management of hyperthyroidism during pregnancy and lactation. Eur J
Endocrinol. 2011; 164(6): 871-6.
6. Clementi M, Di Gianantonio E, Cassina M, Leoncini E, Botto LD, Mastroiacovo P. Treatment of
hyperthyroidism in pregnancy and birth defects. J Clin Endocrinol Metab. 2010; 95(11):
E337-41.
7. Di Gianantonio E, Schaefer C, Mastroiacovo PP, Cournot MP, Benedicenti F, Reuvers M, et al.
Adverse effects of prenatal methimazole exposure. Teratology. 2001; 64(5): 262-6.
8. Clementi M, Di Gianantonio E, Pelo E, Mammi I, Basile RT, Tenconi R. Methimazole
embryopathy: delineation of the phenotype. Am J Med Genet. 1999; 83(1): 43-6.
9. Rivkees SA. Pediatric Graves' disease: controversies in management. Horm Res Paediatr. 2010;
74(5): 305-11.
10. Bowman P, Osborne NJ, Sturley R, Vaidya B. Carbimazole embryopathy: implications for the
choice of antithyroid drugs in pregnancy. QJM, 2012; 105(2): 189-93.
11. Yoshihara A, Noh J, Yamaguchi T, Ohye H, Sato S, Sekiya K, et al. Treatment of graves'
disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of
congenital malformation. J Clin Endocrinol Metab. 2012; 97(7): 2396-403.
12. Wing DA, Millar LK, Koonings PP, Montoro MN, Mestman JH. A comparison of
propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy. Am J
Obstet Gynecol. 1994; 170(1 Pt 1): 90-5.
13. Korelitz JJ, McNally DL, Masters MN, Li SX, Xu Y, Rivkees SA. Prevalence of thyrotoxicosis,
antithyroid medication use, and complications among pregnant women in the United States.
Thyroid. 2013;23(6):758-65.
14. van Veenendaal NR, Ulmer B, Boskovski MT, Fang X, Khokha MK, Wendler CC, et al.
Embryonic exposure to propylthiouracil disrupts left-right patterning in Xenopus embryos.
FASEB J. 2013; 27(2): 684-91.
15. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The
Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement:
guidelines for reporting observational studies. Lancet. 2007; 370(9596): 1453-7.
16. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: Updated guidelines for
reporting parallel group randomised trials. J Pharmacol Pharmacother. 2010; 1(2): 100-7.
17. Andersen SL, Olsen J, Wu CS, Laurberg P. Birth defects after early pregnancy use of
antithyroid drugs: a Danish nationwide study. J Clin Endocrinol Metab. 2013; 98(11): 4373-81.
18. Chen CH, Xirasagar S, Lin CC, Wang LH, Kou YR, Lin HC. Risk of adverse perinatal
outcomes with antithyroid treatment during pregnancy: a nationwide population-based study.
BJOG. 2011; 118(11): 1365-73.
19. Rosenfeld H, Ornoy A, Shechtman S, Diav-Citrin O. Pregnancy outcome, thyroid dysfunction
and fetal goitre after in utero exposure to propylthiouracil: a controlled cohort study. Br J Clin
Pharmacol. 2009; 68(4): 609-17.
20. Momotani N, Ito K, Hamada N, Ban Y, Nishikawa Y, Mimura T. Maternal hyperthyroidism and
congenital malformation in the offspring. Clin Endocrinol (Oxf). 1984; 20(6): 695-700.
21. Clark SM, Saade GR, Snodgrass WR, Hankins GD. Pharmacokinetics and pharmacotherapy of
thionamides in pregnancy. Ther Drug Monit. 2006; 28(4): 477-83.
22. Cooper DS. Antithyroid drugs. N Engl J Med. 2005; 352(9): 905-17.
23. Cooper DS, Laurberg P. Hyperthyroidism in pregnancy. Lancet Diabetes Endocrinol. 2013; 1(3):
238-49.
24. Emiliano AB, Governale L, Parks M, Cooper DS. Shifts in propylthiouracil and methimazole
prescribing practices: antithyroid drug use in the United States from 1991 to 2008. J Clin
Endocrinol Metab. 2010; 95(5): 2227-33.
25. Hackmon R, Blichowski M, Koren G. The safety of methimazole and propylthiouracil in
pregnancy: a systematic review. J Obstet Gynaecol Can. 2012; 34(11): 1077-86.
26. Clementi M, Gianantonio E. Therapeutic drug monitoring of antithyroid drugs in pregnancy: the
knowledge gaps. Ther Drug Monit. 2006; 28(4): 576.
27. Diav-Citrin O, Ornoy A. Teratogen update: antithyroid drugs-methimazole, carbimazole, and
propylthiouracil. Teratology. 2002; 65(1): 38-44.
Table 1. Characteristics of 7 studies included in the review
Study
Year
Study type
Participants
Controls
Treatment
Birth defects
Andersen
2013
Cohort
1661 women with
811730 women without
Treated with
urinary system
PTU or MMI
hyperthyroidism
anti-thyroid
malformation,
treatment
3543 women without ATD use
medication in
malformations in the face
159 women with
1066 women without
early
and neck region, choanal
shifts in MMI and
hyperthyroidism
pregnancy
atresia, esophageal atresia
703 women with
14150 women without
Treated with
cleft lip and palate, limb
PTU or MMI
hyperthyroidism
PTU/MMI for
defects, heart defects, down
Treatment
2127 women without ATD use
at least 30 days syndrome, hypospadias
1023 women with
634858 women without
Prescriptions
congenital anomalies of
PTU or MMI
hyperthyroidism
(PTU/MMI)
eye, complex heart
et al
PTU
Chen et al
2011
Korelitz et 2012
al
Case-control
Case-control
treatment
5932 women without ATD use
filled within 6
anomalies, atrial ventricular
126 women with
months during
septal defects, anomalies of
shifts in PTU and
the pregnancy
respiratory system,
MMI
anomalies of congenital
organs;
Rosenfeld
2009
Cohort
et al
80 women with
1066 women without
Treated with
developmental dysplasia of
PTU treatment
hyperthyroidism
PTU between
the hip
4 and 13 weeks
of gestation
Yoshihara
et al
2012
Case-control
2630 women with
1906 women without ATD use
Treated with
aplasia cutis congenital,
PTU or MMI
PTU/MMI
omphalocele, symptomatic
treatment
during the first
omphalomesenteric duct
trimester
anomaly
Wing et al
Momotani
et al
1994
1984
Case-control
Case-control
135 women with
43 women without ATD use
Treated with
severe pulmonic stenosis,
PTU or MMI
99 women without
PTU or with
ventricular septal defect,
treatment
hyperthyroidism
MMI
patent ductus arteriosus
117 women with
350 women without
Treated with
Malformation of the
MMI treatment
hyperthyroidism
MMI during
ear-lobe, omphalocele,
the first
imperforate anus,
trimester
anencephaly, harelip,
polydactyly