Stine Linding Andersen

Birth Defects After Early Pregnancy Use of Antithyroid Drugs: A Danish Nationwide Study

INTRODUCTION 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. OBJECTIVE 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. METHODS 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. RESULTS 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]). CONCLUSIONS 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.

Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: a Danish nationwide cohort study

To examine the association between maternal hyper‐ and hypothyroidism and the risk of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in the child.

THERAPY OF ENDOCRINE DISEASE: Antithyroid drug use in early pregnancy and birth defects: time windows of relative safety and high risk?

BACKGROUND Antithyroid drugs (ATDs) may have teratogenic effects when used in early pregnancy. OBJECTIVE To review the association between the time period of ATD exposure in early pregnancy and the development of birth defects. METHODS We identified publications on birth defects after early pregnancy exposure to the ATDs methimazole (MMI; and its prodrug carbimazole (CMZ)) and propylthiouracil (PTU). Cases of birth defects after ATD treatment had been initiated or terminated within the first 10 weeks of pregnancy were identified and studied in detail. RESULTS A total of 92 publications were read in detail. Two recent large controlled studies showed ATD-associated birth defects in 2-3% of exposed children, and MMI/CMZ-associated defects were often severe. Out of the total number of publications, 17 included cases of birth defects with early pregnancy stop/start of ATD treatment, and these cases suggested that the high risk was confined to gestational weeks 6-10, which is the major period of organogenesis. Thus, the cases reported suggest that the risk of birth defects could be minimized if pregnant women terminate ATD intake before gestational week 6. CONCLUSION Both MMI and PTU use in early pregnancy may lead to birth defects in 2-3% of the exposed children. MMI-associated defects are often severe. Proposals are given on how to minimize the risk of birth defects in fertile women treated for hyperthyroidism with ATDs.

Low Birth Weight in Children Born to Mothers with Hyperthyroidism and High Birth Weight in Hypothyroidism, whereas Preterm Birth Is Common in Both Conditions: A Danish National Hospital Register Study

Objectives: Maternal hyper- and hypothyroidism have been associated with increased risk of adverse pregnancy outcomes, but studies have led to inconsistent results. We aimed to identify children born to mothers with a hospital-recorded diagnosis of thyroid dysfunction in Denmark and to study the association with gestational age at delivery and birth weight of the child. Study Design: Population-based cohort study using Danish nationwide registers. All singleton live births in Denmark between January 1, 1978 and December 31, 2006 were identified and stratified by maternal diagnosis of hyper- or hypothyroidism registered in the Danish National Hospital Register before January 1, 2007. Results: Maternal first-time diagnosis of thyroid dysfunction before, during or after pregnancy was registered in 32,809 (2.0%) of the singleton live births (n = 1,638,338). Maternal diagnosis of hyperthyroidism (adjusted OR 1.22, 95% CI 1.15-1.30) and hypothyroidism (adjusted OR 1.17, 95% CI 1.08-1.27) were associated with increased risk of preterm birth. Moreover, birth weight in children born to mothers with a diagnosis of hyperthyroidism was lower (adjusted difference -51 g, 95% CI -58 to -43 g) and higher in relation to maternal hypothyroidism (adjusted difference 20 g, 95% CI 10-30 g). Hyperthyroidism was associated with small-for-gestational-age (adjusted OR 1.15, 95% CI 1.10-1.20) and hypothyroidism with large-for-gestational-age children (adjusted OR 1.24, 95% CI 1.17-1.31). Conclusions: Based on Danish nationwide registers, both maternal hyper- and hypothyroidism were associated with increased risk of preterm birth. Actual birth weight of the child and birth weight for gestational age were low if the mother had a diagnosis of hyperthyroidism and high if the diagnosis was hypothyroidism.

Severity of Birth Defects After Propylthiouracil Exposure in Early Pregnancy

BACKGROUND Propylthiouracil (PTU) used in the treatment of maternal hyperthyroidism in early pregnancy may be associated with a higher prevalence of birth defects in the face and neck region and in the urinary system but the severity of these complications remains to be elucidated. METHODS Review of hospital-registered cases of birth defects in the face and neck region and in the urinary system after PTU exposure in early pregnancy. We obtained information on maternal redeemed prescription of PTU and child diagnosis of birth defect from nationwide registers for all children born in Denmark between 1996 and 2008 (n=817,093). The children were followed until December 31, 2010 (median age, 8.3 years) and the Cox proportional hazards model was used to estimate adjusted hazard ratio (HR) with 95% confidence interval (CI) for having a birth defect after PTU exposure versus nonexposed children (n=811,730). RESULTS Fourteen cases of birth defects were identified in the face and neck region and in the urinary system after PTU exposure in early pregnancy; 11 children were exposed to PTU only (n=564), whereas 3 children were born to mothers who switched from methimazole (MMI)/carbimazole (CMZ) to PTU in early pregnancy (n=159). Among children exposed to PTU only, the adjusted HR for having a birth defect in the face and neck region was 4.92 (95% CI 2.04-11.86) and in the urinary system 2.73 (1.22-6.07). Looking into details of the 14 cases, 7 children were diagnosed with a birth defect in the face and neck region (preauricular and branchial sinus/fistula/cyst) and 7 children had a birth defect in the urinary system (single cyst of kidney and hydronephrosis). Surgical treatment was registered in 6 of the cases with a birth defect in the face and neck region and 3 of the cases with a birth defect in the urinary system. Two of the children with a birth defect in the urinary system also had other birth defects (genital organs). CONCLUSIONS We report details on possible PTU-associated birth defects. They tend to be less severe than the defects observed after MMI/CMZ exposure. Yet, the majority of affected children had to undergo surgery.

Screening for overt thyroid disease in early pregnancy may be preferable to searching for small aberrations in thyroid function tests

Thyroid hormones are important regulators of foetal development, and in recent years, there has been much focus on the screening and treatment of pregnant women for even small aberrations in thyroid function tests. We searched PubMed for publications on thyroid function and pregnancy outcomes including child cognition, and included references from the retrieved articles. Both small aberrations in thyroid function tests in early pregnancy and an increase in risk of pregnancy complications may be caused by a functional change in the uteroplacental unit. Thus, the association found in several studies between small thyroid test abnormalities and pregnancy complications may be due to confounding, and thyroid hormone therapy will have no effect. On the other hand, screening of thyroid function in early pregnancy may identify 200–300 women with undiagnosed overt hypothyroidism per 100 000 pregnancies, which is at least five times more than the number of hypothyroid newborns identified by screening. A number of studies indicate that untreated overt thyroid disease in pregnancy may lead to complications. The potential benefit of screening and early therapy is supported by evidence, indicating that even severe maternal hypothyroidism does not lead to neurocognitive deficiencies in the child, if the condition is detected and treated during the first half of pregnancy. Screening and therapy for overt thyroid dysfunction in early pregnancy may be indicated, rather than focusing on identifying and treating small aberrations in thyroid function tests.

Iodine Concentrations in Milk and in Urine During Breastfeeding Are Differently Affected by Maternal Fluid Intake

BACKGROUND Breastfed infants are dependent on iodine transport into breast milk for production of thyroid hormones. Thyroid hormones are important regulators of brain development. It has been considered whether breast milk iodine concentration (MIC) could be predicted by maternal urinary iodine concentration (UIC), but reports on correlations have been inconsistent. We used urinary creatinine concentration as a proxy for maternal fluid intake and speculated if this might differently influence UIC and MIC. METHODS We examined 127 breastfeeding women after the introduction of the mandatory iodine fortification of salt in Denmark. Maternal spot urine and a breast milk sample were obtained at a median of 31 days after delivery (interquartile range: 25-42 days), and the women were asked about intake of iodine containing supplements postpartum. RESULTS Median UIC was 72 μg/L (46-107 μg/L) and higher in iodine-supplemented mothers (47.2% of participants); 83 μg/L (63-127 μg/L) versus 65 μg/L (40-91 μg/L), p=0.004. Median MIC was 83 μg/L (61-125 μg/L) and also higher in iodine-supplemented mothers; 112 μg/L (80-154 μg/L) versus 72 μg/L (47-87 μg/L), p<0.001. There was a weak correlation between UIC and MIC (r=0.28, p=0.015). A strong correlation was present between UIC and urinary creatinine concentration (r=0.76, p<0.001), whereas urinary creatinine concentration was not correlated to MIC (r=-0.049, p=0.58). When UIC and urinary creatinine were used to estimate 24-h urinary iodine excretion, the correlation between this estimate and breast milk iodine excretion was stronger (r=0.48, p<0.001). CONCLUSIONS Intake of an iodine supplement should be recommended in Danish breastfeeding women. Our results indicate that UIC, but not MIC, depends on maternal fluid intake and that maternal estimated 24-h iodine excretion may be a better indicator of iodine supply to the breastfed infant than UIC.

Foetal programming by maternal thyroid disease

Foetal programming is an emerging concept that links a wide range of exposures during foetal life to later development of disease. Thyroid disorders are common in women of reproductive age, and careful management of pregnant women suffering from thyroid disease is important considering the crucial role of thyroid hormones during early brain development. It is possible that maternal thyroid dysfunction in pregnancy may lead to structural and/or functional changes during foetal brain development. Such an effect could later predispose the offspring to an increased risk of neurologic or psychiatric disease. We recently observed that children born to mothers with thyroid dysfunction had an increased risk of developing seizure disorders, autism spectrum disorders, attention‐deficit hyperactivity disorders and psychiatric disease in adolescence and young adulthood. In the review, we discuss the concept of potential foetal programming by maternal thyroid disease.

Dynamics and Predictors of Serum TSH and fT4 Reference Limits in Early Pregnancy: A Study Within the Danish National Birth Cohort

CONTEXT Thyroid hormones are important developmental factors and levels should be adequate both in the pregnant woman and in the fetus. However, there is no consensus on maternal thyroid test reference limits in early pregnancy. OBJECTIVE Estimation of week-to-week changes in and predictors of TSH and free T4 (fT4) reference limits in the first trimester of pregnancy. DESIGN Measurement of TSH and fT4 in biobank sera collected in pregnancy weeks 5-19 from a random sample of the Danish National Birth Cohort that enrolled 101 032 pregnant in 1996-2002. SETTING National cohort of pregnant women. PARTICIPANTS Healthy participants (n = 6671) were identified and individual characteristics retrieved using interview data and data from Danish national health registers. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Reference limits for TSH and fT4 in each first trimester pregnancy week and predictors of these reference limits. RESULTS TSH reference limits were very variable. Up to and including week 6, nonpregnancy reference limits could be used. In weeks 9-12, TSH upper reference limit was approximately 0.4 mU/L lower than the nonpregnancy upper limit. The TSH lower reference limit was approximately 0.1 mU/L. fT4 variations were reverse to those of TSH, but changes were small with approximately 4% higher reference limits during the weeks 9-12. TSH upper reference limit was lower in multiparous women and women with lower iodine intake but higher in obese women. fT4 was lower in smokers. CONCLUSIONS TSH reference limits differ widely in the first trimester of pregnancy. The use of a uniform set of reference limits is an inordinate simplification that will lead to frequent misclassification and possibly to incorrect choice of therapy.

Antithyroid Drug Side Effects in the Population and in Pregnancy

OBJECTIVE Methimazole (MMI) and propylthiouracil (PTU) are both associated with birth defects and may also rarely be associated with agranulocytosis and liver failure. The frequency of these side effects when antithyroid drugs (ATDs) are used in the population in general or in pregnancy remains to be elucidated. DESIGN All individuals registered as the parent of a live-born child in Denmark, 1973–2008, were identified (n = 2 299 952) and studied from 1995 through 2010 for the use of ATDs. Outcomes were agranulocytosis, liver failure, and birth defects in their offspring. To evaluate the frequency of these side effects associated with the use of ATDs in pregnancy, all live-born pregnancies (n = 830 680), 1996–2008, were identified in a subanalysis. RESULTS In the population studied, 28 998 individuals redeemed prescriptions of ATDs (exposure in 2115 pregnancies), which was associated with 45 cases of agranulocytosis (one in pregnancy) and 10 cases of liver failure (one in pregnancy). This corresponded to 41 and 11 cases of agranulocytosis and liver failure per 5 million inhabitants during a 10-year period (agranulocytosis: 0.16% of ATDs exposed [MMI: 0.11% vs PTU: 0.27%, P = .02]; liver failure: 0.03% of ATDs exposed [MMI: 0.03% vs PTU: 0.05%, P = .4]). The majority (83%) developed the side effect within 3 months of ATD treatment and 25% during hyperthyroidism relapse. The use of ATDs in pregnancy was associated with birth defects in 3.4% of exposed children (44 cases per 5 million inhabitants per 10 y), and the frequency of birth defects after ATD exposure was 75 times higher than both maternal agranulocytosis and liver failure in pregnancy. CONCLUSIONS In the Danish population in general, ATDs associated birth defects and agranulocytosis had similar frequencies and were more common than liver failure, whereas for the use of ATDs in pregnancy, birth defects were dominant. The burden of side effects to the use of ATDs can be reduced by restricting the use of ATDs in early pregnancy.