Opinion
VIEWPOINT
Alex Stagnaro-Green, MD, MHPE University of Illinois, College of Medicine at Rockford.
Screening Pregnant Women for Overt Thyroid Disease Thyroid disease, defined as hormonal abnormalities or the presence of thyroid antibodies in euthyroid women during pregnancy, is associated with maternal, fetal, and newborn complications.1 The relationship between overt thyroid disease (hypothyroidism or hyperthyroidism) and adverse pregnancy outcomes has been known for decades. However, it has only been in the last 20 years that research has linked subclinical hypothyroidism to miscarriage, preterm delivery, preeclampsia, gestational hypertension, and perinatal mortality. Furthermore, since 1990 an association has been reported between thyroid antibody positivity (thyroid peroxidase antibody, thyroglobulin antibody, or both) in euthyroid women and spontaneous miscarriage, recurrent abortion, and preterm delivery. These findings have resulted in discussion regarding the benefits and risks of universal screening for thyroid disease during pregnancy. According to the World Health Organization, the institution of universal screening requires fulfilling the following criteria: (1) the condition is common, (2) a screening tool for the condition is readily available, reliable, inexpensive, and acceptable to the patient, (3) an intervention is available that favorably influences the disease and has limited adverse effects, (4) the costs of screening and intervention are costeffective, and (5) there is an agreed-upon policy on whom to treat. This Viewpoint discusses these criteria and suggests that sufficient evidence exists for the institution of routine screening to detect and treat overt thyroid disease during pregnancy. However, there are insufficient data to support universal screening to detect subclinical hypothyroidism or the presence of thyroid antibodies.
Disease Prevalence
Corresponding Author: Alex StagnaroGreen, MD, MHPE, University of IllinoisCollege of Medicine at Rockford, 1601 Parkview Ave, Rockford, IL 61107-1897 ([email protected]). jama.com
Multiple studies have evaluated the prevalence of overt and subclinical thyroid disease during pregnancy. Overt thyroid disease is defined as an abnormal thyrotropin level with an abnormal free thyroxine (FT4) level, and subclinical thyroid disease is defined as an abnormal thyrotropin level with an FT4 level in the normal range. In studies of pregnant women, 0.3% to 0.5% have overt hypothyroidism2 and 0.4% have overt hyperthyroidism. Identifying the prevalence of subclinical hypothyroidism and hyperthyroidism is more complex. Human chorionic gonadotropin levels, which peak in the first trimester, cross-react at the thyrotropin receptor resulting in a decrease in the normal reference range. Guidelines on thyroid disorders during pregnancy from the American Thyroid Association2 and Endocrine Society3 published in 2011 and 2012, respectively, recommend an upper limit of thyrotropin in the first trimester of 2.5 mIU/L. Whereas previous studies based on an upper thyrotropin limit of 4.2 mIU/L reported a prevalence of subclinical hypothyroidism of 2% to 3%,
more recent studies report a higher prevalence, some exceeding 15%.4 It is difficult, if not impossible, to know the prevalence of subclinical hyperthyroidism because human chorionic gonadotropin levels result in a physiological suppression of thyrotropin in more than 15% of women in the first trimester. Moreover, between 10% and 20% of women who are euthyroid and become pregnant have positive thyroid antibody results.
Screening Tool Characteristics In a scenario in which screening is instituted, testing would consist of a thyrotropin level followed by measurement of FT4if the thyrotropin level is abnormal. Both thyrotropin and FT4 assays are readily accessible and inexpensive. Thyrotropin levels are highly reliable and accurate. Although pregnancy may affect FT4levels, both the American Thyroid Association and Endocrine Society suggest that commercially available FT4 assays have sufficient reliability to recommend their use.2,3 Thyroid antibody testing is also highly reliable and low cost.
Complications Associated With Hypothyroidism and Thyroid Antibodies Complications related to overt hypothyroidism (spontaneous abortion, fetal death, preeclampsia, gestational hypertension,andcretinism)andoverthyperthyroidism(preterm delivery, neonatal death, stillbirth, preeclampsia, and heart failure) can be avoided with appropriate therapy. In a retrospective analysis, pregnant women with overt hypothyroidism who were inadequately treated, defined as neverachievingathyrotropinlevelof4mIU/Lorlowerduring pregnancy, had a rate of spontaneous abortion of 60% vs 0% among women who received adequate therapy.5 Similarly, women with overt thyrotoxicosis during pregnancywhowereeithernottreatedorinadequatelytreated had an increase in perinatal mortality, maternal heart failure,andpretermdeliverycomparedwiththyrotoxicwomen who received adequate intervention.6 Treatment of overt thyroid disease is universally recommended, regardlessofpregnancystatus,andthusaplacebo-controlledtrial of the efficacy of treatment for overt thyroid disease during pregnancy is not required. No study has definitively documented an association between subclinical hyperthyroidism and adverse maternaland/orfetalevents.However,arobustbodyofevidence has demonstrated an association between subclinical hypothyroidism and adverse pregnancy outcomes. Nevertheless, the data on the outcome of treating subclinical hypothyroidism during pregnancy are limited and have yieldedmixedresults.Inaprospectivetrialoffirst-trimester pregnant women who had a thyrotropin level above 2.5 mIU/L and had positive thyroid peroxidase antibody results, levothyroxine decreased maternal and fetal ad(Reprinted) JAMA February 10, 2015 Volume 313, Number 6
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Georgian Court University User on 05/11/2015
565
Opinion Viewpoint
verseoutcomescomparedwithanuntreatedcontrolgroupwhosefirsttrimester serum samples had been frozen and not assayed until after delivery.7 Another study found no difference in IQ of the offspring of pregnant women with subclinical hypothyroidism who received levothyroxine compared with the offspring of women who were not treated.8 Multiple observational studies have documented an association between thyroid antibodies and both miscarriage and preterm delivery. The only study that evaluated the results of treatment in euthyroid,thyroidperoxidaseantibody–positivewomendemonstrated a significant decrease in both miscarriage and preterm delivery.9
Cost-effectivenessofScreeningforThyroidDiseaseinPregnancy A 2012 study evaluated the cost-effectiveness of universal screening for the detection of thyroid disease during pregnancy vs either targeted screening (focusing on women at high risk for thyroid disease) or no screening.10 In a sensitivity analysis, screening solely for overt hypothyroidism had a cost-effectiveness ratio of $6776 /QALY (quality adjusted life-year) when compared with no screening and $7335/QALY when compared with targeted screening, indicating that universal screening for overt hypothyroidism is cost-effective. In the United States, screening strategies that cost less than $50 000/QALY are considered cost-effective. For comparative purposes, the costeffectiveness ratio for amniocentesis is $15 000/QALY and screening for gestational diabetes mellitus is $12 078/QALY.
Approach to Screening for Overt Thyroid Disease Screening for overt thyroid disease during pregnancy meets the criteria required for the institution of universal screening. Overt hypothyroidism is relatively common (0.3%-0.5% of pregnant women),2 has serious adverse maternal and fetal outcomes that can be prevented with levothyroxine therapy, and is cost-effective. In addition, it appears that at no additional cost, universal screening will detect pregnant women with overt hyperthyroidism that will allow for treatment and decrease maternal and fetal adverse outcomes. At present, the majority of pregnant women are not screened for thyroid disease. A potential alternative to universal screening is case finding, the selective screening of women with risk factors for thyroid disease. However, case finding has been shown to lack sensitivity, potentially missing 30% to 80% of women with thyroid dysfunction. The preferred test to use to screen pregnant women for thyroid disease is measurement of thyrotropin, followed by an FT4 level ARTICLE INFORMATION Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. REFERENCES 1. Männistö T, Mendola P, Grewal J, et al. Thyroid diseases and adverse pregnancy outcomes in a contemporary US cohort. J Clin Endocrinol Metab. 2013;98(7):2725-2733. 2. Stagnaro-Green A, Abalovich M, Alexander E, et al; American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011;21 (10):1081-1125.
566
if the thyrotropin value is abnormal. Screening should occur as early in pregnancy as feasible. Women with overt hypothyroidism or hyperthyroidism should be treated. Why then has routine screening not been implemented? The major barrier may be insufficient data surrounding the management of subclinical hypothyroidism in pregnancy, which will be detected more frequently through screening than overt hypothyroidism, the primary disease target. Screening to diagnose subclinical hypothyroidism or thyroid antibodies is not justified because the available data are insufficient to conclude whether treatment for subclinical hypothyroidism will decrease maternal and fetal adverse events reported in observational studies. Additional data from randomized clinical trials are required to address this question. However, the lack of data regarding the treatment of subclinical hypothyroidism should not affect the decision to screen for overt thyroid disease. Arguments against routine screening include that health professionals may not appreciate that physiological suppression of thyrotropin occurs in the first trimester, and they may be unclear about how to advise pregnant women with subclinical hypothyroidism. The response to these concerns involves education of health care professionals about thyroid physiology during pregnancy and educating patients about the present state of medical knowledge, which does not support routine treatment of subclinical disease. This information can be included in the electronic health record, thereby providing easy access for clinicians. Other concerns regarding routine screening may include that the prevalences of diseases already screened for in pregnancy are extremely low; that once screening for thyroid disease has begun it will be impossible to discontinue even if results of prospective ongoing randomized studies on treating subclinical hypothyroidism during pregnancy show no benefit; or that possible medicolegal risks may arise for failure to screen.
Conclusions Overt thyroid disease, present in almost 1% of all pregnant women, is as common as some and more common than many of the pregnancy-related diseases for which routine screening is performed. Furthermore, the outcome of intervention studies on subclinical hypothyroidism will not adversely influence the need for routine thyroid screening. Even if the studies demonstrate no benefit of treating subclinical hypothyroidism, the available evidence supports routine screening of pregnant women for overt thyroid disease.
3. De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(8):2543-2565. 4. Blatt AJ, Nakamoto JM, Kaufman HW. National status of testing for hypothyroidism during pregnancy and postpartum. J Clin Endocrinol Metab. 2012;97(3):777-784. 5. Abalovich M, Gutierrez S, Alcaraz G, et al. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid. 2002;12(1):63-68. 6. Davis LE, Lucas MJ, Hankins GDV, et al. Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol. 1989;160(1):63-70. 7. Negro R, Schwartz A, Gismondi R, et al. Universal screening versus case finding for detection and
treatment of thyroid hormonal dysfunction during pregnancy. J Clin Endocrinol Metab. 2010;95(4): 1699-1707. 8. Lazarus JH, Bestwick JP, Channon S, et al. Antenatal thyroid screening and childhood cognitive function. N Engl J Med. 2012;366(6):493501. 9. Negro R, Formoso G, Mangieri T, et al. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease. J Clin Endocrinol Metab. 2006;91(7):2587-2591. 10. Dosiou C, Barnes J, Schwartz A, et al. Cost-effectiveness of universal and risk-based screening for autoimmune thyroid disease in pregnant women. J Clin Endocrinol Metab. 2012;97 (5):1536-1546.
JAMA February 10, 2015 Volume 313, Number 6 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Georgian Court University User on 05/11/2015
jama.com
VIEWPOINT
Alex Stagnaro-Green, MD, MHPE University of Illinois, College of Medicine at Rockford.
Screening Pregnant Women for Overt Thyroid Disease Thyroid disease, defined as hormonal abnormalities or the presence of thyroid antibodies in euthyroid women during pregnancy, is associated with maternal, fetal, and newborn complications.1 The relationship between overt thyroid disease (hypothyroidism or hyperthyroidism) and adverse pregnancy outcomes has been known for decades. However, it has only been in the last 20 years that research has linked subclinical hypothyroidism to miscarriage, preterm delivery, preeclampsia, gestational hypertension, and perinatal mortality. Furthermore, since 1990 an association has been reported between thyroid antibody positivity (thyroid peroxidase antibody, thyroglobulin antibody, or both) in euthyroid women and spontaneous miscarriage, recurrent abortion, and preterm delivery. These findings have resulted in discussion regarding the benefits and risks of universal screening for thyroid disease during pregnancy. According to the World Health Organization, the institution of universal screening requires fulfilling the following criteria: (1) the condition is common, (2) a screening tool for the condition is readily available, reliable, inexpensive, and acceptable to the patient, (3) an intervention is available that favorably influences the disease and has limited adverse effects, (4) the costs of screening and intervention are costeffective, and (5) there is an agreed-upon policy on whom to treat. This Viewpoint discusses these criteria and suggests that sufficient evidence exists for the institution of routine screening to detect and treat overt thyroid disease during pregnancy. However, there are insufficient data to support universal screening to detect subclinical hypothyroidism or the presence of thyroid antibodies.
Disease Prevalence
Corresponding Author: Alex StagnaroGreen, MD, MHPE, University of IllinoisCollege of Medicine at Rockford, 1601 Parkview Ave, Rockford, IL 61107-1897 ([email protected]). jama.com
Multiple studies have evaluated the prevalence of overt and subclinical thyroid disease during pregnancy. Overt thyroid disease is defined as an abnormal thyrotropin level with an abnormal free thyroxine (FT4) level, and subclinical thyroid disease is defined as an abnormal thyrotropin level with an FT4 level in the normal range. In studies of pregnant women, 0.3% to 0.5% have overt hypothyroidism2 and 0.4% have overt hyperthyroidism. Identifying the prevalence of subclinical hypothyroidism and hyperthyroidism is more complex. Human chorionic gonadotropin levels, which peak in the first trimester, cross-react at the thyrotropin receptor resulting in a decrease in the normal reference range. Guidelines on thyroid disorders during pregnancy from the American Thyroid Association2 and Endocrine Society3 published in 2011 and 2012, respectively, recommend an upper limit of thyrotropin in the first trimester of 2.5 mIU/L. Whereas previous studies based on an upper thyrotropin limit of 4.2 mIU/L reported a prevalence of subclinical hypothyroidism of 2% to 3%,
more recent studies report a higher prevalence, some exceeding 15%.4 It is difficult, if not impossible, to know the prevalence of subclinical hyperthyroidism because human chorionic gonadotropin levels result in a physiological suppression of thyrotropin in more than 15% of women in the first trimester. Moreover, between 10% and 20% of women who are euthyroid and become pregnant have positive thyroid antibody results.
Screening Tool Characteristics In a scenario in which screening is instituted, testing would consist of a thyrotropin level followed by measurement of FT4if the thyrotropin level is abnormal. Both thyrotropin and FT4 assays are readily accessible and inexpensive. Thyrotropin levels are highly reliable and accurate. Although pregnancy may affect FT4levels, both the American Thyroid Association and Endocrine Society suggest that commercially available FT4 assays have sufficient reliability to recommend their use.2,3 Thyroid antibody testing is also highly reliable and low cost.
Complications Associated With Hypothyroidism and Thyroid Antibodies Complications related to overt hypothyroidism (spontaneous abortion, fetal death, preeclampsia, gestational hypertension,andcretinism)andoverthyperthyroidism(preterm delivery, neonatal death, stillbirth, preeclampsia, and heart failure) can be avoided with appropriate therapy. In a retrospective analysis, pregnant women with overt hypothyroidism who were inadequately treated, defined as neverachievingathyrotropinlevelof4mIU/Lorlowerduring pregnancy, had a rate of spontaneous abortion of 60% vs 0% among women who received adequate therapy.5 Similarly, women with overt thyrotoxicosis during pregnancywhowereeithernottreatedorinadequatelytreated had an increase in perinatal mortality, maternal heart failure,andpretermdeliverycomparedwiththyrotoxicwomen who received adequate intervention.6 Treatment of overt thyroid disease is universally recommended, regardlessofpregnancystatus,andthusaplacebo-controlledtrial of the efficacy of treatment for overt thyroid disease during pregnancy is not required. No study has definitively documented an association between subclinical hyperthyroidism and adverse maternaland/orfetalevents.However,arobustbodyofevidence has demonstrated an association between subclinical hypothyroidism and adverse pregnancy outcomes. Nevertheless, the data on the outcome of treating subclinical hypothyroidism during pregnancy are limited and have yieldedmixedresults.Inaprospectivetrialoffirst-trimester pregnant women who had a thyrotropin level above 2.5 mIU/L and had positive thyroid peroxidase antibody results, levothyroxine decreased maternal and fetal ad(Reprinted) JAMA February 10, 2015 Volume 313, Number 6
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Georgian Court University User on 05/11/2015
565
Opinion Viewpoint
verseoutcomescomparedwithanuntreatedcontrolgroupwhosefirsttrimester serum samples had been frozen and not assayed until after delivery.7 Another study found no difference in IQ of the offspring of pregnant women with subclinical hypothyroidism who received levothyroxine compared with the offspring of women who were not treated.8 Multiple observational studies have documented an association between thyroid antibodies and both miscarriage and preterm delivery. The only study that evaluated the results of treatment in euthyroid,thyroidperoxidaseantibody–positivewomendemonstrated a significant decrease in both miscarriage and preterm delivery.9
Cost-effectivenessofScreeningforThyroidDiseaseinPregnancy A 2012 study evaluated the cost-effectiveness of universal screening for the detection of thyroid disease during pregnancy vs either targeted screening (focusing on women at high risk for thyroid disease) or no screening.10 In a sensitivity analysis, screening solely for overt hypothyroidism had a cost-effectiveness ratio of $6776 /QALY (quality adjusted life-year) when compared with no screening and $7335/QALY when compared with targeted screening, indicating that universal screening for overt hypothyroidism is cost-effective. In the United States, screening strategies that cost less than $50 000/QALY are considered cost-effective. For comparative purposes, the costeffectiveness ratio for amniocentesis is $15 000/QALY and screening for gestational diabetes mellitus is $12 078/QALY.
Approach to Screening for Overt Thyroid Disease Screening for overt thyroid disease during pregnancy meets the criteria required for the institution of universal screening. Overt hypothyroidism is relatively common (0.3%-0.5% of pregnant women),2 has serious adverse maternal and fetal outcomes that can be prevented with levothyroxine therapy, and is cost-effective. In addition, it appears that at no additional cost, universal screening will detect pregnant women with overt hyperthyroidism that will allow for treatment and decrease maternal and fetal adverse outcomes. At present, the majority of pregnant women are not screened for thyroid disease. A potential alternative to universal screening is case finding, the selective screening of women with risk factors for thyroid disease. However, case finding has been shown to lack sensitivity, potentially missing 30% to 80% of women with thyroid dysfunction. The preferred test to use to screen pregnant women for thyroid disease is measurement of thyrotropin, followed by an FT4 level ARTICLE INFORMATION Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. REFERENCES 1. Männistö T, Mendola P, Grewal J, et al. Thyroid diseases and adverse pregnancy outcomes in a contemporary US cohort. J Clin Endocrinol Metab. 2013;98(7):2725-2733. 2. Stagnaro-Green A, Abalovich M, Alexander E, et al; American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011;21 (10):1081-1125.
566
if the thyrotropin value is abnormal. Screening should occur as early in pregnancy as feasible. Women with overt hypothyroidism or hyperthyroidism should be treated. Why then has routine screening not been implemented? The major barrier may be insufficient data surrounding the management of subclinical hypothyroidism in pregnancy, which will be detected more frequently through screening than overt hypothyroidism, the primary disease target. Screening to diagnose subclinical hypothyroidism or thyroid antibodies is not justified because the available data are insufficient to conclude whether treatment for subclinical hypothyroidism will decrease maternal and fetal adverse events reported in observational studies. Additional data from randomized clinical trials are required to address this question. However, the lack of data regarding the treatment of subclinical hypothyroidism should not affect the decision to screen for overt thyroid disease. Arguments against routine screening include that health professionals may not appreciate that physiological suppression of thyrotropin occurs in the first trimester, and they may be unclear about how to advise pregnant women with subclinical hypothyroidism. The response to these concerns involves education of health care professionals about thyroid physiology during pregnancy and educating patients about the present state of medical knowledge, which does not support routine treatment of subclinical disease. This information can be included in the electronic health record, thereby providing easy access for clinicians. Other concerns regarding routine screening may include that the prevalences of diseases already screened for in pregnancy are extremely low; that once screening for thyroid disease has begun it will be impossible to discontinue even if results of prospective ongoing randomized studies on treating subclinical hypothyroidism during pregnancy show no benefit; or that possible medicolegal risks may arise for failure to screen.
Conclusions Overt thyroid disease, present in almost 1% of all pregnant women, is as common as some and more common than many of the pregnancy-related diseases for which routine screening is performed. Furthermore, the outcome of intervention studies on subclinical hypothyroidism will not adversely influence the need for routine thyroid screening. Even if the studies demonstrate no benefit of treating subclinical hypothyroidism, the available evidence supports routine screening of pregnant women for overt thyroid disease.
3. De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(8):2543-2565. 4. Blatt AJ, Nakamoto JM, Kaufman HW. National status of testing for hypothyroidism during pregnancy and postpartum. J Clin Endocrinol Metab. 2012;97(3):777-784. 5. Abalovich M, Gutierrez S, Alcaraz G, et al. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid. 2002;12(1):63-68. 6. Davis LE, Lucas MJ, Hankins GDV, et al. Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol. 1989;160(1):63-70. 7. Negro R, Schwartz A, Gismondi R, et al. Universal screening versus case finding for detection and
treatment of thyroid hormonal dysfunction during pregnancy. J Clin Endocrinol Metab. 2010;95(4): 1699-1707. 8. Lazarus JH, Bestwick JP, Channon S, et al. Antenatal thyroid screening and childhood cognitive function. N Engl J Med. 2012;366(6):493501. 9. Negro R, Formoso G, Mangieri T, et al. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease. J Clin Endocrinol Metab. 2006;91(7):2587-2591. 10. Dosiou C, Barnes J, Schwartz A, et al. Cost-effectiveness of universal and risk-based screening for autoimmune thyroid disease in pregnant women. J Clin Endocrinol Metab. 2012;97 (5):1536-1546.
JAMA February 10, 2015 Volume 313, Number 6 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Georgian Court University User on 05/11/2015
jama.com
