methimazole and Abnormalities--Drug-Induced

The risk of congenital anomalies following in utero exposure to thionamide antithyroid drugs (ATDs) is unresolved. Observational studies are contradictory and existing meta-analyses predate and preclude more recent studies. We undertook an updated meta-analysis of congenital anomaly risk in women exposed to carbimazole or methimazole (CMZ/MMI), propylthiouracil (PTU), or untreated hyperthyroidism in pregnancy.. We searched Medline, Embase, and the Cochrane database for articles published up till August 2021. We pooled separate crude and adjusted risk estimates using random effects models and subgroup analyses to address heterogeneity.. We identified 16 cohort studies comprising 5957, 15,785, and 15,666 exposures to CMZ/MMI, PTU, and untreated hyperthyroidism, respectively. Compared to nondisease controls, adjusted risk ratio (RR) and 95% confidence intervals (95% CIs) for congenital anomalies was increased for CMZ/MMI (RR, 1.28; 95% CI, 1.06-1.54) and PTU (RR, 1.16; 95% CI, 1.08-1.25). Crude risk for CMZ/MMI was increased relative to PTU (RR, 1.20; 95% CI, 1.01-1.43). Increased risk was also seen with exposure to both CMZ/MMI and PTU, that is, women who switched ATDs in pregnancy (RR, 1.51; 95% CI, 1.14-1.99). However, the timing of ATD switch was highly variable and included prepregnancy switches in some studies. The excess number of anomalies per 1000 live births was 17.2 for patients exposed to CMZ/MMI, 9.8, for PTU exposure, and 31.4 for exposure to both CMZ/MMI and PTU. Risk in the untreated group did not differ from control or ATD groups. The untreated group was however highly heterogeneous in terms of thyroid status. Subgroup analysis showed more positive associations in studies with >500 exposures and up to 1-year follow-up.. ATD therapy carries a small risk of congenital anomalies which is higher for CMZ/MMI than for PTU and does not appear to be reduced by switching ATDs in pregnancy. Due to key limitations in the available data, further studies will be required to clarify the risks associated with untreated hyperthyroidism and with switching ATDs in pregnancy.

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Carbimazole; Female; Humans; Hyperthyroidism; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil

Maternal antithyroid drug (ATD) use during pregnancy has been associated with an increased risk of birth defects in offspring. Uncertainty remains on the size of this risk and how it compares to untreated hyperthyroidism due to methodological limitations of previous studies.. Systematic review of MEDLINE and EMBASE identifying observational studies examining ATD use during pregnancy and risk of birth defects by 28 August 2020. Data were extracted on study characteristics, effect estimates and comparator groups. Adjusted effect estimates were pooled using a random-effects generic inverse variance method and absolute risk calculated.. Seven cohort studies and 1 case-control study involving 6 212 322 pregnancies and 388 976 birth defects were identified reporting regression effect estimates. Compared to an unexposed population comparison, the association between ATD use during pregnancy and birth defects in offspring was: adjusted risk ratio (aRR) 1.16 95% confidence interval (CI) 1.08-1.25 for propylthiouracil (PTU); aRR 1.28 95%CI 1.06-1.54 for methimazole/carbimazole (MMI/CMZ); aRR 1.51, 95%CI 1.16-1.97 for both MMI/CMZ and PTU; and aRR 1.15 95%CI 1.02-1.29 for untreated hyperthyroidism. The excess risk of any and major birth defects per 1000, respectively, was: 10.2 and 1.3 for PTU; 17.8 and 2.3 for MMI/CMZ; 32.5 and 4.1 for both MMI/CMZ and PTU; and 9.6 and 1.2 for untreated hyperthyroidism.. When appropriately analysed the risk of birth defects associated with ATD use in pregnancy is attenuated. Although still elevated, the risk of birth defects is smallest with PTU compared to MMI/CMZ and may be similar to that of untreated hyperthyroidism.

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Case-Control Studies; Female; Humans; Hyperthyroidism; Methimazole; Observational Studies as Topic; Pregnancy; Pregnancy Complications; Propylthiouracil

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Carbimazole; Female; Humans; Hyperthyroidism; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil

Thyroid disorders including hyperthyroidism are common during pregnancy. Untreated hyperthyroidism can result in adverse outcomes for pregnancy.. Iodine, propylthiouracil (PTU), carbimazole (CMZ), and methimazole (MMI) are common medications for hyperthyroidism treatment. The literature regarding antithyroid medication use in pregnancy and breastfeeding is reviewed.. Animal studies for PTU have suggested congenital anomalies while animal studies for MMI have only indicated adverse outcomes at higher doses than used in humans. Epidemiological studies have noted an increased risk of congenital anomalies for PTU less often than CMZ or MMI but the epidemiological evidence remains mixed. A pattern of anomalies has been described for CMZ and MMI, from both case and epidemiological studies, including choanal atresia, aplasia cutis congenita, and other facial, heart, gastrointestinal, and skin anomalies. Closer examination of cases indicates that a few cases of the anomalies have occurred without exposure to CMZ or MMI and outside of the proposed critical period. PTU has a small risk of hepatotoxicity which rarely results in liver transplantation and death. Some authors have suggested that PTU be prescribed in early pregnancy and switched to MMI in late pregnancy. Untreated hyperthyroidism, from either a lack of medications or switching medications during the first trimester, may also increase the chance of congenital anomalies. Multiple case studies and larger epidemiological studies have failed to provide clear, consistent outcomes for the use of PTU, CMZ, and MMI in pregnancy. MMI and PTU both enter the breastmilk in small amounts.. Additional research is needed to assist in the medical management and exposure counseling of pregnant and breastfeeding women with hyperthyroidism.

Topics: Abnormalities, Drug-Induced; Animals; Antithyroid Agents; Female; Humans; Methimazole; Pregnancy; Propylthiouracil; Teratogens

Many conditions that require frequent medication use are common during pregnancy. The purpose of this article is to list some of the most common of these disorders and to discuss the risk to the developing fetus of the medications used most frequently to treat them. Included are drugs used for the treatment of asthma, nausea and vomiting, hyperthyroidism, pain and fever, and depression during pregnancy.

Topics: Abnormalities, Drug-Induced; Acetaminophen; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Analgesics, Non-Narcotic; Anti-Asthmatic Agents; Antidepressive Agents; Antiemetics; Antithyroid Agents; Asthma; Congenital Abnormalities; Depressive Disorder; Female; Humans; Hyperthyroidism; Leukotriene Antagonists; Maternal-Fetal Exchange; Methimazole; Morning Sickness; Ondansetron; Pregnancy; Pregnancy Complications; Propylthiouracil; Teratogens

The aim of this study was to determine the effect of exposure to different antithyroid drugs during pregnancy on the incidence of neonatal congenital malformations.. A meta-analysis was performed to compare the incidence of neonatal congenital malformations after exposure to different antithyroid drugs during pregnancy. Twelve studies that met the inclusion criteria were included in this meta-analysis. PubMed, Embase, and CENTRAL databases were searched from inception until January 2017. Study designs included case-control studies, prospective cohort studies, and retrospective cohort studies.. Twelve studies involving 8028 participants with exposure to different antithyroid drugs during pregnancy were included in this study; however, only 10 studies involving 5059 participants involved exposure to different antithyroid drugs exactly during pregnancy. Our results indicated that exposure to methimazole (MMI)/carbimazole (CMZ) only during pregnancy significantly increased the risk of neonatal congenital malformations compared to no antithyroid drug exposure (OR 1.88; 95%CI 1.33 to 2.65; P = 0.0004). No differences were observed between propylthiouracil (PTU) exposure and no antithyroid drug exposure only during pregnancy (OR 0.81; 95%CI 0.58 to 1.15; P = 0.24). Exposure to MMI/CMZ only during pregnancy significantly increased the risk of neonatal congenital malformations compared to that associated with exposure to PTU (OR 1.90; 95%CI 1.30 to 2.78; P = 0.001).. For pregnant women with hyperthyroidism, exposure to MMI/CMZ significantly increased the incidence of neonatal congenital malformations compared to exposure to PTU and no antithyroid drug exposure; however, no differences were observed between PTU exposure and no antithyroid drug exposure.

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Female; Humans; Infant, Newborn; Methimazole; Pregnancy; Propylthiouracil

The potencies of resorcinol, 6-propylthiouracil (PTU) and methimazole (MMI) for inducing developmental toxicity and neurotoxicity were compared in pregnant rats, regarded as valid model for human thyroid toxicity. Profound differences on maternal thyroid hormone levels (THs), maternal toxicity as well as developmental and neurotoxicity sequelae occurred. Resorcinol affected none of those end points. PTU and MMI caused significant effects. Therapy with either PTU or MMI during the first trimester of human pregnancy can cause reductions of maternal THs, accompanied by disruptions of prenatal development. Clinical MMI studies show sporadic evidence of teratogenic effects, with equivocal relation to thyroid peroxidase (TPO) inhibition. In recent decades no MMI associated prenatal toxicity has been reported, an outcome possibly related to carefully managed therapy. Orally administered resorcinol was rapidly absorbed, metabolized and excreted and was undetectable in the thyroid. In contrast, PTU or MMI accumulated. Resorcinol's potency to inhibit TPO was profoundly lower than that of PTU or MMI. Quantum chemical calculations may explain low resorcinol reactivity with TPO. Thus, distinctions in the target organ and the TPO inhibitory potency between these chemicals are likely contributing to different reductions of maternal THs levels and affecting the potency to cause developmental toxicity and neurotoxicity.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Autoantigens; Biomarkers; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Gestational Age; Humans; Iodide Peroxidase; Iron-Binding Proteins; Methimazole; Neurotoxicity Syndromes; Pregnancy; Propylthiouracil; Rats; Resorcinols; Risk Assessment; Thyroid Gland; Thyroid Hormones

Hyperthyroidism affects about 0.2%-2.7% of all pregnancies, and is commonly managed with antithyroid drugs (ATDs). However, previous studies about the effects of ATDs on congenital anomalies are controversial. Therefore, the present meta-analysis was performed to explore the risk of congenital anomalies in children exposed to ATDs in-utero.. Embase, Pubmed, Web of Knowledge, and BIOSIS Citation Index were searched to find out studies about congenital anomalies in children exposed to ATDs in-utero reported up to May 2014. The references cited by the retrieved articles were also searched. The relative risks (RRs) and confidence intervals (CIs) for the individual studies were pooled by fixed effects models, and heterogeneity was analyzed by chi-square and I2 tests.. Eight studies met the inclusion criteria. Exposure to propylthiouracil (PTU), methimazole/carbimazole (MMI/CMZ), and PTU & MMI/CMZ was investigated in 7, 7 and 2 studies, respectively. The pooled RR was 1.20 (95%CI: 1.02-1.42), 1.64 (95%CI: 1.39-1.92), and 1.83 (95%CI: 1.30-2.56) for congenital anomalies after exposure to PTU, MMI/CMZ, and PTU & MMI/CMZ, respectively.. The meta-analysis suggests that exposure to ATDs in-utero increases the risk of congenital anomalies. The use of ATDs in pregnancy should be limited when possible. Further research is needed to delineate the exact teratogenic risk for particular congenital anomaly.

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Carbimazole; Cohort Studies; Databases, Factual; Female; Humans; Hyperthyroidism; Infant, Newborn; Methimazole; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Risk

To evaluate the association of either propylthiouracil or methimazole treatment for hyperthyroidism during pregnancy with congenital malformations, relevant studies were identified by searching Medline, PubMed, the Cochrane Library and EMBASE. We intended to include randomized controlled trials, but no such trials were identified. Thus, we included cohort studies and case-control studies in this meta-analysis. A total of 7 studies were included in the meta-analyses. The results revealed an increased risk of birth defects among the group of pregnant women with hyperthyroidism treated with methimazole compared with the control group (odds ratio 1.76, 95% confidence interval 1.47-2.10) or the non-exposed group (odds ratio 1.71, 95% confidence interval 1.39-2.10). A maternal shift between methimazole and propylthiouracil was associated with an increased odds ratio of birth defects (odds ratio 1.88, 95% confidence interval 1.27-2.77). An equal risk of birth defects was observed between the group of pregnant women with hyperthyroidism treated with propylthiouracil and the non-exposed group (odds ratio 1.18, 95% confidence interval 0.97-1.42). There was only a slight trend towards an increased risk of congenital malformations in infants whose mothers were treated with propylthiouracil compared with in infants whose mothers were healthy controls (odds ratio 1.29, 95% confidence interval 1.07-1.55). The children of women receiving methimazole treatment showed an increased risk of adverse fetal outcomes relative to those of mothers receiving propylthiouracil treatment. We found that propylthiouracil was a safer choice for treating pregnant women with hyperthyroidism according to the risk of birth defects but that a shift between methimazole and propylthiouracil failed to provide protection against birth defects.

Topics: Abnormalities, Drug-Induced; Adult; Antithyroid Agents; Case-Control Studies; Cohort Studies; Confidence Intervals; Female; Humans; Hyperthyroidism; Infant, Newborn; Male; Methimazole; Odds Ratio; Pregnancy; Pregnancy Complications; Propylthiouracil; Risk

The treatment of choice for hyperthyroidism in pregnancy is antithyroid drugs, but the potential risk of birth defects is of major concern. For the use of thiamazole and carbimazole, there is consistent evidence of an increased risk of birth defects, which are often severe. For the use of propylthiouracil, the evidence is less clear. These birth defects may be less severe, and a Danish study which included all birth defects diagnosed before the age of two years showed an increased risk of birth defects in the face and neck region and in the urinary system after the use of propylthouracil.

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Carbimazole; Female; Humans; Hyperthyroidism; Infant, Newborn; Methimazole; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First; Propylthiouracil; Risk Factors

Hyperthyroidism is one of the most common endocrine disorders in pregnant women, and it can severely complicate the course and outcome of pregnancy. Methimazole (MMI) and propylthiouracil (PTU) are the standard anti-thyroid drugs used in the treatment of hyperthyroidism in pregnancy. Traditionally, MMI has been considered to have clearer evidence of teratogenicity than PTU. Recent studies suggest that PTU can be hepatotoxic, leading to a United States Food and Drug Administration "black box alert." We wished to systematically review the effects of PTU and MMI during pregnancy, and to compare maternal and fetal safety.. We conducted a systematic search of PubMed, EMBASE, TOXNET, TOXLINK, DART, Medscape, EBSCO, and Google. Both English and non-English publications were included. We excluded studies using anti-thyroid therapies other than PTU and MMI, studies not allowing interpretation of results, and abstracts of meetings.. Overall, insufficient statistical power precluded determination of accurate rates of either MMI teratogenicity or PTU hepatotoxicity in cohort studies. However, a case-control study helped identify the relative risk of MMI-induced choanal atresia. A second case-control study failed to show that aplasia cutis congenita is associated with MMI. PTU has been associated with a rare but serious form of hepatic failure.. MMI causes a specific pattern of rare teratogenic effects after first trimester exposure, while PTU therapy may be followed by rare but severe hepatotoxic sequelae. It is therefore appropriate to use PTU to treat maternal hyperthyroidism during the first trimester of pregnancy, and to switch to MMI for the remainder of the pregnancy.

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Case-Control Studies; Chemical and Drug Induced Liver Injury; Female; Gestational Age; Humans; Hyperthyroidism; Methimazole; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First; Propylthiouracil

Despite being a common condition in pregnancy, and despite propylthiouracil (PTU) being perceived as safer than methimazole, there are virtually no epidemiological controlled studies on malformation rate an neurobehavioral outcomes with the former. This knowledge gap must be filled to ensure fetal safety.

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Drug Administration Schedule; Drug Monitoring; Female; Humans; Infant, Newborn; Knowledge; Maternal-Fetal Exchange; Methimazole; Milk, Human; Pregnancy; Propylthiouracil; Thyrotoxicosis

First cause of hyperthyroidism among women of childbearing age, Graves' disease raises the risk of maternal and fetal complications, including eclampsia, cardiac failure, abortion, prematurity, fetal death, all of which can be avoided if maternal hyperthyroidism is closely controlled. The risk of transplacental hyperthyroidism has been shown to correlate to the titre of anti-TSH receptor antibodies and has to be evaluated not only in women treated for Graves' disease during pregnancy, but also in women who have previously received radio iodine treatment or undergone surgery for Graves' disease: TSH-receptor antibodies may indeed remain at a high level several years after initial treatment. Both methimazole and propylthiouracil are equally effective to restore maternal euthyroidism. Accumulation of case-reports relating congenital malformations (mostly aplasia cutis, but in some cases, severe malformations) among the offspring of methimazole-treated women suggests the possibility of a teratogenic effect of methimazole. Despite the fact that the link between severe congenital defects and methimazole exposure during pregnancy is not formally established, propylthiouracil should be preferred to methimazole for the treatment of young hyperthyroid women.

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Female; Graves Disease; Humans; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil

We report on a further case of congenital anomalies in a child exposed to methimazole during the first trimester of pregnancy (from first to seventh gestational week), and define a specific malformation pattern related to prenatal methimazole exposure and consisting of choanal and esophageal atresia, scalp defects, minor facial anomalies and psychomotor delay.

Topics: Abnormalities, Drug-Induced; Adult; Antithyroid Agents; Child, Preschool; Choanal Atresia; Esophageal Atresia; Female; Graves Disease; Humans; Male; Maternal-Fetal Exchange; Methimazole; Phenotype; Pregnancy; Pregnancy Trimester, First; Teratogens

Therapy of thyroid dysfunction needs a close cooperation between endocrinologist and gynecologist. In addition to a number of metabolic changes during pregnancy, the diaplacentar transfer of different substances (thionamides, antibodies) has to be considered. Pregnant women with overt and subclinical hypothyroidism should be treated using L-Thyroxine with the bTSH between 1 and 2 mU/l. Many of the women need an increase of the L-Thyroxine dose during pregnancy. Overt hyperthyroidism (mostly due to Graves' disease) has to be treated immediately after diagnosis using thionamides. Because thionamides cross the placenta, the dose should be as low as possible with the fT4 in upper level and bTSH in the lower level of normal range. Most studies show, that both methimazole (MI) and propylthiouracil (PTU) can be used in pregnancy. Although PTU is preferred especially in the USA, an advantage of PTU over MI is not proven. Surgery is necessary in only few cases of hyperthyroidism during pregnancy with the optimal time for surgery during the second trimester. In case of subclinical hyperthyroidism and HCG induced hyperthyroidism several controls of thyroid function should be performed to decide whether treatment is necessary.

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Dose-Response Relationship, Drug; Female; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Risk Factors; Thyroid Function Tests; Thyroxine

Thioamide therapy has improved the outcome of pregnancies complicated by maternal hyperthyroidism, without long-term effects on cognitive and somatic development. However, there remain questions concerning whether these drugs, especially methimazole (MMI), may be associated with aplasia cutis congenita (ACC) and how best to avoid impairment of fetal thyroid function during their use. We report an example of ACC and review the relevant literature. We conclude that there is insufficient evidence either to establish or eliminate a direct causal relationship between ACC and MMI use. Since propylthiouracil is an equally effective antithyroid agent and has not been associated with ACC, it is the preferred thioamide for hyperthyroidism during pregnancy. Our review also indicates that impairment of neonatal thyroid function may be minimized by using a thioamide dose that is just sufficient to maintain the maternal serum free thyroxine concentration in the high normal or slightly thyrotoxic range.

Topics: Abnormalities, Drug-Induced; Adult; Antithyroid Agents; Child Development; Female; Humans; Hyperthyroidism; Infant, Newborn; Maternal-Fetal Exchange; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Skin Abnormalities; Teratogens; Thyroid Diseases; Thyroxine

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Drug Administration Schedule; Female; Humans; Hyperthyroidism; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil

To control hyperthyroidism due to Graves' disease, antithyroid drugs should be administered. Several studies have shown that exposure to methimazole (MMI) during the first trimester of pregnancy increases the incidence of specific congenital anomalies that are collectively referred to as MMI embryopathy. Congenital anomalies associated with exposure to propylthiouracil (PTU) have also recently been reported.. This study investigated whether substituting potassium iodide (KI) for MMI in the first trimester would result in a lower incidence of major congenital anomalies than continuing treatment with MMI alone. The cases of 283 women with Graves' disease (GD) were reviewed whose treatment was switched from MMI to KI in the first trimester (iodine group), as well as the cases of 1333 patients treated with MMI alone (MMI group) for comparison. Another major outcome of interest was the incidence of neonatal thyroid dysfunction. The subjects of the analysis of major congenital anomalies and neonatal thyroid dysfunction were live-born infants.. The incidence of major anomalies was 4/260 (1.53%) in the iodine group, which was significantly lower than the incidence of 47/1134 (4.14%) in the MMI group. Two neonates in the iodine group had anomalies consistent with MMI embryopathy (0.8%), as opposed to 18 neonates in the MMI group (1.6%). None of the neonates exposed to KI had thyroid dysfunction or goiter.. Substituting KI for MMI as a means of controlling hyperthyroidism in GD patients during the first trimester may reduce the incidence of congenital anomalies, at least in iodine-sufficient regions.

Topics: Abnormalities, Drug-Induced; Adult; Antithyroid Agents; Drug Substitution; Female; Graves Disease; Humans; Incidence; Japan; Methimazole; Potassium Iodide; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First; Retrospective Studies; Thyrotropin; Thyroxine; Treatment Outcome; Triiodothyronine

The data in the literature suggests that Methimazole (MMI)/Carbimazole (CMZ) embryopathy is rare. This study examined the incidence of CMZ embryopathy in the Hong Kong Chinese population and the factors associated with its development.. Of the 145 pregnant women with hyperthyroidism managed from 2008 to 2010, 29 (20%) had taken CMZ during pregnancy. The presence and details of birth defects, the dosage of CMZ, and the period of exposure during pregnancy were examined in these 29 pregnancies. All cases of CMZ embryopathy in the English literature were reviewed in the same way.. Of the 27 babies (93.1%) with known outcome, 3 had aplasia cutis and 1 had an omphalocele in addition, and 1 affected baby had a sibling with aplasia cutis and patent vitellointestinal duct. The incidence of CMZ embryopathy in our study group is 11.1%. Amongst the 21 cases of CMZ embryopathy in the literature, 85% were exposed to a CMZ dosage of ≥20 mg/day, and the minimum duration of exposure being 7 weeks from last menstrual period. The most common abnormality is ectodermal anomaly (62%), followed by oro-nasal anomaly (48%), facial dysmorphism (38%), gastrointestinal anomaly (33%) and abdominal wall defect (19%). There was no relationship between the type of abnormality and the dosage or duration of exposure to CMZ.. The incidence of CMZ embryopathy in our study group is 11.1%. Critical factors for its development are exposure to a CMZ dosage of ≥20 mg/day before 7 weeks of gestation. Genetic susceptibility may also play a role.

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Asian People; Female; Fetal Diseases; Gestational Age; Graves Disease; Hong Kong; Humans; Incidence; Infant, Newborn; Male; Methimazole; Pregnancy; Pregnancy Complications; Pregnancy Outcome

Hyperthyroidism in pregnant women should be adequately treated to prevent maternal and fetal complications, but teratogenic effects of antithyroid drug (ATD) treatment have been described. Evidence is still lacking in regard to the safety and choice of ATD in early pregnancy.. Our objective was to determine to which degree the use of methimazole (MMI)/carbimazole (CMZ) and propylthiouracil (PTU) in early pregnancy is associated with an increased prevalence of birth defects.. This Danish nationwide register-based cohort study included 817 093 children live-born from 1996 to 2008. Exposure groups were assigned according to maternal ATD use in early pregnancy: PTU (n = 564); MMI/CMZ (n = 1097); MMI/CMZ and PTU (shifted in early pregnancy [n = 159]); no ATD (ATD use, but not in pregnancy [n = 3543]); and nonexposed (never ATD use [n = 811 730]). Multivariate logistic regression was used to estimate adjusted odds ratio (OR) with 95% confidence interval (95% CI) for diagnosis of a birth defect before 2 years of age in exposed versus nonexposed children.. The prevalence of birth defects was high in children exposed to ATD in early pregnancy (PTU, 8.0%; MMI/CMZ, 9.1%; MMI/CMZ and PTU, 10.1%; no ATD, 5.4%; nonexposed, 5.7%; P < .001). Both maternal use of MMI/CMZ (adjusted OR = 1.66 [95% CI 1.35-2.04]) and PTU (1.41 [1.03-1.92]) and maternal shift between MMI/CMZ and PTU in early pregnancy (1.82 [1.08-3.07]) were associated with an increased OR of birth defects. MMI/CMZ and PTU were associated with urinary system malformation, and PTU with malformations in the face and neck region. Choanal atresia, esophageal atresia, omphalocele, omphalomesenteric duct anomalies, and aplasia cutis were common in MMI/CMZ-exposed children (combined, adjusted OR = 21.8 [13.4-35.4]).. Both MMI/CMZ and PTU were associated with birth defects, but the spectrum of malformations differed. More studies are needed to corroborate results in regard to early pregnancy shift from MMI/CMZ to PTU. New ATD with fewer side effects should be developed.

Topics: Abnormalities, Drug-Induced; Adult; Antithyroid Agents; Carbimazole; Denmark; Female; Humans; Hyperthyroidism; Infant, Newborn; Male; Methimazole; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First; Prevalence; Propylthiouracil

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Carbimazole; Female; Humans; Hyperthyroidism; Male; Methimazole; Pregnancy; Propylthiouracil

Propylthiouracil (PTU) is recommended as a first-line antithyroid drug (ATD) during first trimester organogenesis in pregnancy because recent evidence suggests that methimazole (MMI) may be associated with congenital anomalies. However, PTU more commonly causes myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, which usually occurs during prolonged treatment, compared with MMI. We report a case of MPO-ANCA-associated vasculitis in a 35-year-old woman with Graves'disease. Although her thyroid function could be maintained euthyroid by MMI, her ATD was switched to PTU because she wished to become pregnant. The patient presented with flu-like symptoms 8 days after starting PTU and developed hemoptysis and dyspnea at 22 days. Her MPO-ANCA titer was 21 ELISA units (EUs) before PTU treatment but increased to 259 EUs at 22 days after PTU treatment. Her clinical condition improved with the discontinuation of PTU and with immunosuppressive therapy. This case indicated that MPO-ANCA vasculitis occurred within several weeks after the initiation of PTU and that this side effect could be caused by the change from MMI to PTU. Thus, our clinical observation suggests that patients treated with PTU should be carefully monitored for MPO-ANCA titers and variable manifestations of MPO-ANCA-associated vasculitis regardless of the period of administration.

Topics: Abnormalities, Drug-Induced; Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Female; Graves Disease; Humans; Methimazole; Peroxidase; Pregnancy; Pregnancy Complications; Propylthiouracil

Population-based estimates of the prevalence of thyrotoxicosis (TTX), the frequency of antithyroid drug (ATD) use, and risk of adverse events in pregnant women and their infants are lacking. Therefore, our objective was to obtain epidemiologic estimates of these parameters within a large population-based sample of pregnant women with TTX.. A retrospective claims analysis was performed from the MarketScan Commercial Claims and Encounters health insurance database for the period 2005-2009. Women aged 15-44 years, enrolled for at least 2 years, and who had a pregnancy during the study period were included. Diagnosis of TTX was based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes using narrow (TTX-1=ICD 242.0) and broad (TTX-2=ICD 242.0 or 242.9) definitions. ATD use was based on prescriptions filled for propylthiouracil (PTU) or methimazole (MMI). Adverse events in mothers and infants were determined from the ICD-9-CM diagnosis codes recorded on submitted claims.. The database contained 904,497 eligible women. The average yearly prevalence per 1000 pregnant women was 2.46 for TTX-1 and 5.88 for TTX-2. Thirty-nine percent used ATD at any time during the study period. Compared to women without a TTX diagnosis, there was more than a twofold increase for liver disease among women with TTX (odds ratio [OR]=2.08, p<0.001) and a 13% increased risk for congenital anomalies (OR=1.13, p=0.014), but no association was observed with ATD use. The rates of congenital defects (per 1000 infants) associated with ATD use were 55.6 for MMI, 72.1 for PTU, and 65.8 for untreated women with TTX, compared to 58.8 among women without TTX.. There was some indication of an elevated risk of liver disease and congenital anomalies in women with TTX, but the risk did not appear to be related to the ATD use. There seems to be a higher pregnancy termination rate for women with TTX on MMI, which likely reflects elective pregnancy terminations.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Antithyroid Agents; Chemical and Drug Induced Liver Injury; Congenital Abnormalities; Drug Prescriptions; Female; Hepatic Insufficiency; Humans; Infant; Infant, Newborn; Insurance, Health; International Classification of Diseases; Methimazole; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Prevalence; Propylthiouracil; Retrospective Studies; Thyrotoxicosis; United States; Young Adult

Several reports have suggested that propylthiouracil (PTU) may be safer than methimazole (MMI) for treating thyrotoxicosis during pregnancy because congenital malformations have been associated with the use of MMI during pregnancy.. We investigated whether in utero exposure to antithyroid drugs resulted in a higher rate of major malformations than among the infants born to a control group of pregnant women.. We reviewed the cases of women with Graves' disease who became pregnant. The pregnancy outcomes of 6744 women were known, and there were 5967 live births. MMI alone had been used to treat 1426 of the women, and 1578 women had been treated with PTU alone. The 2065 women who had received no medication for the treatment of Graves' disease during the first trimester served as the control group. The remaining women had been treated with potassium iodide, levothyroxine, or more than one drug during the first trimester. The antithyroid drugs were evaluated for associations with congenital malformations.. The overall rate of major anomalies in the MMI group was 4.1% (50 of 1231), and it was significantly higher than the 2.1% (40 of 1906) in the control group (P = 0.002), but there was no increase in the overall rate of major anomalies in the PTU group in comparison with the control group (1.9%; 21 of 1399; P = 0.709). Seven of the 1231 newborns in the MMI group had aplasia cutis congenita, six had an omphalocele, seven had a symptomatic omphalomesenteric duct anomaly, and one had esophageal atresia. Hyperthyroidism in the first trimester of pregnancy did not increase the rate of congenital malformation.. In utero exposure to MMI during the first trimester of pregnancy increased the rate of congenital malformations, and it significantly increased the rate of aplasia cutis congenita, omphalocele, and a symptomatic omphalomesenteric duct anomaly.

Topics: Abnormalities, Drug-Induced; Adult; Antithyroid Agents; Case-Control Studies; Female; Graves Disease; Humans; Infant, Newborn; Live Birth; Methimazole; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Trimester, First; Prenatal Exposure Delayed Effects; Prevalence; Propylthiouracil; Young Adult

Clinical hyperthyroidism is not uncommon in pregnancy, with a reported prevalence of 0.1 to 0.4%. The available antithyroid drugs are propylthiouracil and methimazole/carbimazole.. In this report we examined the association of both drugs with congenital malformations using data from the International Clearinghouse for Birth Defects Surveillance and Research.. The study used a case-affected control analysis and included 18,131 cases with malformations and reported first-trimester exposure to medication. A total of 127 subjects were born to mothers with known first-trimester antithyroid drug exposure.. Among the 52 groups of malformations that were analyzed, situs inversus ± dextrocardia, isolated unilateral kidney a/dysgenesis, and cardiac outflow tract defects were associated with prenatal exposure to propylthiouracil based on three, two, and five cases, respectively. Prenatal exposure to methimazole/carbimazole was significantly associated with choanal atresia, omphalocele, and total situs inversus ± dextrocardia (P < 0.01).. Further studies are required to exhaustively evaluate the associations between propylthiouracil and birth defects because of the low number, the lack of biological plausibility, and the possibility of underdiagnosis. Association between methimazole/carbimazole exposure and omphalocele and choanal atresia is consistent with previous reports and definitely suggests that these malformations could be part of a specific, even if rare, embryopathy.

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Carbimazole; Case-Control Studies; Female; Humans; Hyperthyroidism; Incidence; Methimazole; Odds Ratio; Pregnancy; Pregnancy Complications; Propylthiouracil

Thyrotoxicosis affects 0.2% of pregnant women and antithyroid drugs are the treatment of choice during pregnancy. Several case reports have suggested a relationship between the prenatal use of methimazole (MMI) and choanal atresia in the offspring. However, two epidemiological studies did not find an increased teratogenic risk for MMI. This multicenter case-control study compared the frequency of maternal hyperthyroidism treated with MMI during pregnancy, in children with choanal atresia (cases) and a control group randomly selected (three matched controls according to maternal age for each case). Mothers of cases (N = 61) and controls (N = 183) were interviewed for socio-demographic questions, obstetrical and genetic history, and exposure during pregnancy to different agents; specifically detailed information regarding hyperthyroidism and MMI intake was obtained. Prenatal exposure to maternal hyperthyroidism treated with MMI was identified in 10/61 cases (16.4%) compared to 2/183 (1.1%) in the control group (OR = 17.75; CI95% = 3.49-121.40). Cases and controls did not differ in their parental degree of education, paternal occupation, twinning, maternal parity, and other exposures during pregnancy. Facial features in exposed cases showed some similarities. Our data suggest that prenatal exposure to maternal hyperthyroidism treated with MMI is associated with choanal atresia. In addition, based on our cases and a critical literature review, we propose that the mother's disease might be the causal factor and not the MMI treatment.

Topics: Abnormalities, Drug-Induced; Adolescent; Antithyroid Agents; Argentina; Case-Control Studies; Child; Child, Preschool; Choanal Atresia; Female; Humans; Male; Maternal Exposure; Methimazole; Pregnancy; Thyrotoxicosis

It has been suggested that children prenatally exposed to methimazole may present some features in common but the phenotype remains to be defined. The reported facial features include upward slanted palpebral fissures, arched flared eyebrows and small nose with a broad bridge. Choanal atresia and other anomalies like esophageal atresia and aplasia cutis were also described with this embryopathy. Additionally, developmental delay was reported in some patients along with one of these major malformation. We present a patient with the mentioned facial features, developmental delay and radio-ulnar synostosis whose mother has been exposed to methimazole during pregnancy and any other ethiological cause could be recognize.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Antithyroid Agents; Facies; Humans; Infant; Male; Methimazole; Phenotype; Radiography; Radius; Synostosis; Ulna

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Child, Preschool; Ectodermal Dysplasia; Female; Graves Disease; Humans; Methimazole; Pregnancy

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Choanal Atresia; Female; Graves Disease; Humans; Infant, Newborn; Maternal-Fetal Exchange; Methimazole; Pregnancy; Pregnancy Complications

A newborn male presented with choanal atresia and minor dysmorphic facial features. At 4 years of age he showed delayed speech and language development. His mother had been treated with thiamazole for pre-existing hyperthyroidism during the first 3 months of pregnancy. It is possible that the maternal use of thiamazole caused the congenital anomalies. Embryopathy caused by maternal thiamazole use during pregnancy has been described several times before and is mainly characterised by choanal atresia, oesophageal atresia, minor dysmorphic facial features, growth retardation and delayed psychomotor development. Because the use of propylthiouracil during pregnancy has not been associated with similar effects, it is the treatment of choice for hyperthyroidism during pregnancy. For pregnant women or women who wish to become pregnant, thiamazole should be prescribed only ifpropylthiouracil cannot be used.

Topics: Abnormalities, Drug-Induced; Adult; Antithyroid Agents; Child, Preschool; Developmental Disabilities; Face; Female; Humans; Male; Methimazole; Pregnancy; Pregnancy Trimester, First; Prenatal Exposure Delayed Effects; Teratogens

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Choanal Atresia; Drug Monitoring; Esophageal Atresia; Female; Fetal Diseases; Health Knowledge, Attitudes, Practice; Humans; Infant, Newborn; Methimazole; Pregnancy; Propylthiouracil

In hyperthyroidism-complicated pregnancies, medical therapy is necessary to reach an euthyroid condition, and propylthiouracil (PTU) or methimazole (MMI) are used. These drugs are equally effective, but may cause fetal and neonatal hypothyroidism because they freely cross the placenta. Although PTU has not been significantly associated with embryo-fetal anomalies, it has been suggested that MMI might be responsible for a specific embryopathy.. Two cases of major congenital anomalies after MMI exposure during pregnancy are reported.. PTU should be the drug of choice, and the use of MMI should be restricted to cases with allergic reactions, intolerance, or poor response to PTU.

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Ectodermal Dysplasia; Female; Humans; Hyperthyroidism; Infant, Newborn; Male; Maternal Age; Methimazole; Pregnancy; Pregnancy Complications; Pregnancy, High-Risk; Scalp; Twins

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Embryo, Mammalian; Female; Humans; Methimazole; Pregnancy; Pregnancy Trimester, First

A specific phenotype of methimazole (MMI) induced malformations has recently been postulated. MMI embryopathy is characterized by minor dysmorphic features, choanal atresia and/or esophageal atresia, growth retardation, and developmental delay.. We prospectively studied the outcome of pregnancy in 241 women counseled by 10 Teratology Information Services (TIS) of the European Network of Teratology Information Services (ENTIS) because of MMI exposure, and compared them with those of 1,089 pregnant women referred to TIS because of exposure to nonteratogenic drugs (control group). Information was obtained by mail or telephone interview.. There was no increase in the general rate of major anomalies or of spontaneous or induced abortions in the MMI-exposed group in comparison with the control group. Two newborns were affected with one of the major malformations that are part of the postulated embryopathy.. The results of this study indicate that choanal as well as esophageal atresia may have a higher incidence than expected in fetuses exposed to MMI between 3 and 7 gestational weeks. Until further data are available, thyrotoxicosis should be treated with propylthiouracil, as it is apparently safer for use during the fertile period.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Adult; Age Factors; Body Weight; Cohort Studies; Developmental Disabilities; Esophageal Atresia; Europe; Female; Humans; Infant, Newborn; Information Services; Male; Methimazole; Phenotype; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Teratogens; Time Factors

Topics: Abnormalities, Drug-Induced; Adult; Child, Preschool; Ectodermal Dysplasia; Epilepsy; Face; Female; Fingers; Graves Disease; Humans; Maternal-Fetal Exchange; Methimazole; Nails, Malformed; Pregnancy; Skin Abnormalities

Topics: Abnormalities, Drug-Induced; Adult; Antithyroid Agents; Esophageal Atresia; Female; Humans; Hyperthyroidism; Infant, Newborn; Male; Methimazole; Pregnancy; Pregnancy Complications; Tracheoesophageal Fistula

Topics: Abnormalities, Drug-Induced; Animal Feed; Clenbuterol; Female; Foodborne Diseases; Humans; Infant, Newborn; Methimazole; Pregnancy; Scalp; Spain

We report on 2 newborn infants with esophageal atresia and tracheoesophageal fistula (EA + TEF) born to hyperthyroid mothers receiving methimazole (Tapazol) before and during their entire pregnancies. Both mothers were euthyroid during gestation and developed hydramnios diagnosed during weeks 34 and 33 of gestation. Premature delivery (36.2 weeks of gestation) occurred in one case, and both newborn infants were small for date with palpable goiter; one of them had other associated malformations. Hypothyroidism was diagnosed by laboratory tests in both cases. Corrective surgery was undertaken, but both newborn infants developed septicemia and renal insufficiency and died in the first week of life. The EA + TEF and a normally placed enlarged thyroid gland were confirmed at necropsy. These cases represent a previously unreported example of the association of maternal ingestion of methimazole during pregnancy and EA + TEF.

Topics: Abnormalities, Drug-Induced; Adult; Esophageal Atresia; Female; Humans; Hyperthyroidism; Infant, Newborn; Male; Maternal-Fetal Exchange; Methimazole; Pregnancy; Pregnancy Complications; Tracheoesophageal Fistula

A literature review of individual pregnancies and recent surveys involving large cohorts reveal an association between congenital malformation and maternal hyperthyroidism, suggesting that some aspect of hyperthyroidism or its treatment might compromise the development of the fetus. Experiments have shown that the thyroid antagonist, ethylenethiourea (ETU), causes fetal malformations when administered to pregnant rats, but it is not known whether it is ETU or the imbalance in maternal thyroid hormone which it causes which is the teratogenic agent. Here we employ in vitro culture to determine the possible direct effects on rat embryos of two thyroid antagonists, ETU and methimazole (MMI), the latter being one which is used for treatment of thyrotoxicosis in humans. It was found that ETU can compromise the development of rat embryos in vitro, confirming that ETU has a direct effect on the rat embryo. It was also found that MMI can cause abnormal development of rat embryos in vitro, although the concentration at which MMI disturbs rat embryogenesis is higher than that which is reached in hyperthyroid patients treated with clinical doses of MMI or carbimazole.

Topics: Abnormalities, Drug-Induced; Animals; Embryo, Mammalian; Ethylenethiourea; Hyperthyroidism; Imidazoles; In Vitro Techniques; Methimazole; Rats; Rats, Inbred Strains

A case of aplasia cutis after exposure to methimazole (Tapazole) in early pregnancy is described. Elevated maternal serum alpha-fetoprotein (MSAFP) and amniotic fluid alpha-fetoprotein (AFP) were found. Elevated MSAFP and amniotic fluid AFP in women exposed to methimazole may suggest this rare fetal condition.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Adult; alpha-Fetoproteins; Amniotic Fluid; Female; Humans; Methimazole; Pregnancy; Scalp; Skull

An infant girl with choanal atresia, athelia, minor anomalies, and mild to moderate mental retardation was born to a woman treated for hyperthyroidism throughout pregnancy with methimazole and propranolol. The patient's defects may be due to methimazole teratogenicity or could represent a previously undescribed syndrome affecting ectodermal structures.

Topics: Abnormalities, Drug-Induced; Adult; Breast; Child, Preschool; Choanal Atresia; Female; Follow-Up Studies; Humans; Hyperthyroidism; Infant; Infant, Newborn; Methimazole; Nipples; Pregnancy; Pregnancy Complications; Syndrome

Aplasia cutis congenita, the localized absence of skin at birth, usually is an isolated scalp defect. We examined an infant with aplasia cutis congenita associated with maternal Grave's disease and the use of methimazole during pregnancy. This association was reported twice before. It has certain implications with respect to therapy of pregnant hyperthyroid women.

Topics: Abnormalities, Drug-Induced; Adult; Female; Graves Disease; Humans; Infant, Newborn; Male; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Skin Abnormalities

Six hundred and forty-three neonates from mothers with Graves' disease were examined for major malformations of external organs to compare the influence of maternal hyperthyroidism vs. ingestion of methimazole (MMI) during the first trimester on the incidence of congenital malformations. The subjects were divided into four groups according to maternal therapy and thyroid status during the first trimester as follows: (1) infants whose mothers did not receive MMI and were hyperthyroid (Group 1), (2) infants whose mothers did not receive MMI and were euthyroid (Group 2), (3) infants whose mothers received MMI and were hyperthyroid (Group 3) and (4) infants whose mothers received MMI and were euthyroid (Group 4). The prevalence of malformed infants in these four groups was 6.0% (three of 50), 0.3% (one of 350), 1.7% (two of 117) and 0.0% (none of 126), respectively. The incidence in Group 1 was significantly higher than that in Group 2 (P less than 0.01). There was no discernible dose dependency of MMI on the occurrence of malformations. These findings suggest that maternal uncontrolled hyperthyroidism may cause congenital malformations and that the beneficial role of MMI treatment outweighs its teratogenic effect, if any.

Topics: Abnormalities, Drug-Induced; Congenital Abnormalities; Dose-Response Relationship, Drug; Female; Humans; Hyperthyroidism; Infant, Newborn; Maternal-Fetal Exchange; Methimazole; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First

Topics: Abnormalities, Drug-Induced; Female; Humans; Hyperthyroidism; Infant, Newborn; Methimazole; Pregnancy; Pregnancy Complications; Skin Abnormalities

Topics: Abnormalities, Drug-Induced; Adult; Female; Fetus; Graves Disease; Humans; Infant, Newborn; Japan; Maternal-Fetal Exchange; Methimazole; Pregnancy; Propylthiouracil

Twenty-one women were studied who had received propylthiouracil or methimazole during 26 pregnancies. Four of the infants had a goiter at birth, and 3 of these had neonatal thyrotoxicosis. In 2 children neonatal thyrotoxicosis was not evident at birth because of maternal antithyroid therapy. Five children had congenital defects. Two mothers were responsible for 4 of the children with abnormalities, and both mothers had been treated with thiourea drugs for long periods, ranging from 7 to 11 years. The majority of children who are exposed to these drugs in utero appear to have no subsequent ill effects. However, prolonged therapy with these agents may be undesirable.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Adult; Female; Fetal Blood; Fetal Death; Goiter; Humans; Hyperthyroidism; Infant; Infant, Newborn; Infant, Newborn, Diseases; Long-Acting Thyroid Stimulator; Male; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Scalp; Thyroid Function Tests; Thyroxine