Universal TSH screening to detect hypothyroidism in pregnancy : a comprehensive review

Transcription

1 The University of Toledo The University of Toledo Digital Repository Master s and Doctoral Projects Universal TSH screening to detect hypothyroidism in pregnancy : a comprehensive review Andrea M. Fox The University of Toledo Follow this and additional works at: This Scholarly Project is brought to you for free and open access by The University of Toledo Digital Repository. It has been accepted for inclusion in Master s and Doctoral Projects by an authorized administrator of The University of Toledo Digital Repository. For more information, please see the repository's About page.

2 Universal TSH screening to detect hypothyroidism in pregnancy: A comprehensive review Andrea M. Fox The University of Toledo 2010

3 ii Dedication To my family and friends, who were always available to offer encouraging words and advice. Also, to my boyfriend, Robert Gospodarek whose unending support and confidence were much needed and appreciated.

4 iii Acknowledgments Thank you to my major advisor, Sharon Gentry, PA-C for the numerous renditions, constructive criticism, and encouragement.

5 iv Table of Contents I: Introduction...1 II: Methods...4 III: Thyroid Hormone Physiology...5 IV: Effects of Hypothyroidism...9 V: Treatment...16 VI: Screening...21 VII: Discussion...28 VIII: Conclusion...36 IX: References...37 X: Table...43 XI: Abstract...44

6 1 Introduction Thyroid dysfunction can complicate many physiologic states and is fairly common in the general population. Thyroid disease affects over 27 million Americans, with more than half of those cases being undiagnosed (Marwaha et al., 2008). It is the most common endocrinology disorder affecting women of child-bearing age, and typically manifests during reproductive years (Marwaha et al., 2008). One state in which the thyroid has been proven to cause adverse effects is that of pregnancy. Thyroid hormone dysfunction is further divided into two subcategories, hyper- and hypothyroidism. While both dysfunctions are important, the state of hypothyroidism is considered to be the more serious regarding pregnancy, as it is related to childhood neurodevelopment (Gyamfi, Wapner, & D Alton, 2009). In addition to adverse effects on neurodevelopment, hypothyroidism is known to cause complications which include hypertension, abruption, postpartum hemorrhage, and low birth weight (Harborne, Alexander, Thomson, O Reilly, & Greer, 2005). These complications are most noted in the first trimester of pregnancy in which the fetal thyroid gland is not yet developed and therefore is dependent on maternal thyroid hormone concentrations (Pop et al., 1999). While pregnancy causes normal alterations in maternal thyroid hormone physiology, the average individual does not have such wide fluctuations to elicit complications (Neale, Cootauco, & Burrow, 2007). Due to these changes associated with pregnancy, there is difficulty in detecting those with hypothyroidism (Gyamfi et al., 2009). Additionally, approximately 20-30% of patients with hypothyroidism develop symptoms (LeBeau & Mandel, 2006). This may prevent a clinician from considering the possibility of hypothyroidism, as well as mask symptoms (Neale et al., 2007). These symptoms include fatigue, constipation, cold intolerance,

7 2 moderate weight gain, and muscle cramps, all of which can and are present during a normal pregnancy course (Casey & Leveno, 2006). While symptoms may be vague and nondescript, the effects on the fetus can be substantial and the question of screening prenatally for thyroid hormone levels in the form of a serum TSH value arise. Currently, it is recommended to test for thyroid dysfunction in those considered highrisk, which consists of personal or family history of thyroid disease, medical conditions associated with thyroid disease, and symptomatic individuals (Committee on Patient Safety and Quality Improvement & Committee on Professional Liability, 2007). While this would be effective in diagnosing those with overt hypothyroidism, there would be a chance of missing another form of hypothyroidism, that being subclinical. Subclinical hypothyroidism is estimated to affect 2.3% of pregnancies (Gyamfi et al., 2009) while the overt form has an estimated prevalence of 0.1%-0.3% (Neale et al., 2007). Both forms have similar adverse outcomes associated with pregnancy (Abalovich et al., 2002). This raises the question of universal screening in pregnancy to detect both forms of hypothyroidism in order to broaden the range of thyroid disease detected. This rationale is linked to both the prevalence of subclinical hypothyroidism as well as the potential benefits of treatment (Committee on Patient Safety and Quality Improvement & Committee on Professional Liability, 2007). It is important to examine the need to screen all individuals because in the United States, each year a minimum of 12,000-15,000 infants are born to mothers with inadequately treated or undetected hypothyroidism, which may implicate complications later in life (Allan et al., 2000). It is also important to detect both overt and subclinical forms, as both are linked with adverse pregnancy outcomes and the majority of those identified as hypothyroid in the United States would have the subclinical form (Casey & Leveno, 2006).

8 3 Currently, universal screening is not recommended because there lacks proof that neurodevelopment would improve in infants born to treated hypothyroid mothers (Gyamfi et al., 2009). Although treatment has been proven effective in mothers with overt hypothyroidism, treatment for the subclinical form is currently being evaluated (Casey & Leveno 2006). In addition to treatment efficacy, further factors must also be considered when evaluating the need to screen, such as cost-effectiveness.

9 4 Methods Research was conducted on the following databases: MEDLINE (PubMed), Academic Search Premiere (EBSCOhost), MD Consult, UpToDate, Cochrane Library, and the Science/Social Science Citation Index. The following terms were used: Thyroid Hormone, Pregnancy, Screening, Subclinical Hypothyroidism, Thyroid Dysfunction, Thyroid Disease, TSH, and free T4. Combinations of the listed terms were also used. Designs first considered were systematic reviews, critically-appraised topics, and randomized-controlled trials. In order to represent a comprehensive review, critically-appraised individual articles and cohort studies were also included. Restrictions were placed on languages other than English, publications before the year 1999, research involving individuals with a known thyroid disorder or a thyroid disorder of the autoimmune etiology, as well as case studies and expert opinion articles. Research completed in the United States or another country with an iodine status similar to that of the United States was included. In regards to analysis of data, all studies used chemoimunnoassays to determine TSH values. While not all studies utilized the same company to assay TSH, the overwhelming majority used Immulite 2000 third generation chemiluminescent assay produced by Diagnostic Services Corporation in Los Angeles, California. All studies also used and maintained a p-value of 0.05 to indicate level of significance.

10 5 Thyroid Hormone Physiology The thyroid hormones T3 and T4 are synthesized by the thyroid gland with the help of dietary iodine, in the form of iodide or iodate (Goldman & Ausiello, 2008). Iodine is actively taken up by the thyroid gland in exchange for sodium, oxidized, and one or two molecules are bound to tyrosol to form monoiodotyrosine or diiodotyrosine. These residues are then coupled together to form tri-iodothyronine (T3) or thyroxine (T4). T3 and T4 are released by the thyroid gland as described above and circulate throughout the body in either bound or free forms. More than 99% of hormones circulating are bound, with the primary binding protein being thyroxinebinding globulin (TBG). These binding proteins serve to maintain a euthyroid state, as the free form of circulating hormone is the active form. The majority of the thyroid s function is carried out by T3 because the receptor binding capacity and biologic activity of T3 is eight-fold greater than that of T4. Therefore, T4 is converted to T3 by target tissues while circulating, making 80% of the T3 present in tissues being derived from T4 (Goldman & Ausiello, 2008). The thyroid gland is under constant endocrine control from the hypothalamic-pituitary axis. Thyroid Releasing Hormone (TRH) is secreted by the hypothalamus and stimulates the pituitary to release Thyroid-Stimulating Hormone (TSH), which then travels to the thyroid gland to increase secretion of T3 and T4 (Goldman & Ausiello, 2008). Concurrently, the release of T3 and T4 regulate the secretion of TRH and TSH from the hypothalamus and pituitary, respectfully. That is, when T3 and T4 are low, TRH and TSH are secreted in order to maintain normal levels of thyroid hormone. The opposite is true when there are low amounts of T3 and T4 in the body (Goldman & Ausiello, 2008). The goal of any mechanism in the body is to maintain homeostasis, which is the reason T3 and T4 assist in regulating their own secretion. Thyroid dysfunction can occur at any of these pathways, with the most commonly analyzed

11 6 processes being those of TSH, T3, and T4 values. TSH is expressed as one value, whereas both T3 and T4 are separated into total or free quantities. This is to differentiate between the amount of active or free hormone and the total amount available to the body. Therefore when documented, ft3/4 indicates the free hormone level and tt3/4 indicates the total hormone level. T4 is easier to measure, and is therefore used more often than T3 in detecting thyroid dysfunction (Goldman & Ausiello, 2008). T4 and T3 assays are typically drawn only if the TSH levels are abnormal in order to verify the presence of a thyroid dysfunction. TSH assays are the primary tests used for diagnosis of thyroid disorders (Baskin et al., 2002). Hypothyroidism results from decreased secretion of the thyroid hormone from the thyroid gland itself (Baskin et al., 2002). Overt hypothyroidism is defined as an elevated TSH and a low ft4 level, while the subclinical form is defined as a moderately elevated TSH with low to normal ft4 levels (Goldman & Ausiello, 2008). A third form of hypothyroidism can also be present, which is termed isolated hypothyroxinemia, meaning TSH levels are normal with low ft4. Symptoms of hypothyroidism are fairly nonspecific with an insidious onset, and may include fatigue, weight gain, cold intolerance, hoarseness, constipation, myalgias, weakness, and mild memory lapse (Goldman & Ausiello, 2008). Upon physical examination, the thyroid gland may be normal, enlarged, or non-palpable in size with varying textures (Goldman & Ausiello, 2008). Because the symptoms, onset, and physical exam findings greatly vary and are relatively nonspecific, it is difficult to diagnose an individual with hypothyroidism in a non-pregnant individual, making a diagnosis of hypothyroidism in a pregnant individual increasingly difficult (Goldman & Ausiello, 2008). Thyroid functioning is altered during the state of pregnancy, as there are many physiologic changes associated with the endocrine system that in turn affect the thyroid gland as

12 7 well as hormone secretion (Neale et al., 2007). These include increased levels of estrogen causing increased TBG, as well as an increase in the pregnancy hormone hcg causing partial inhibition of the pituitary. This partial pituitary inhibition causes decreased TSH, and an increase in T3 and T4 secretion. Additionally, there is a decreased amount of circulating iodine available to mothers and their fetuses due to decreased intestinal absorption, increased maternal clearance, and fetal use (Casey & Leveno, 2006; Neale et al., 2007). Because of these adaptations, the thyroid gland is expected to increase in size by between 10% and 20% (Neto, De Almeida, DaCosta, & Vaisman, 2007). Pregnant mothers are the sole provider of thyroid hormone to the fetus until 12 weeks gestation, at which time the fetal thyroid gland begins concentrating iodine and synthesizing hormone on its own (Casey & Leveno 2006). While the fetus is able to provide some hormone, the maternal hormones are needed as a supplement until approximately 36 weeks, when the fetal gland is functioning at the level of an adult (Neale et al., 2007). Throughout pregnancy the fetus central nervous system (CNS) is continually developing, with the most influential time being the first trimester, which correlates with the time of complete dependence on maternal thyroid hormone (Neto et al., 2007). Additionally, the development of a fetus nervous system occurs in two main steps, the first being during the second trimester and the second during the third. During these steps multiplication, migration, and myelinization of nerve cells occur when the majority of T3 and T4 are maternally supplied. During a normal euthyroid pregnancy, free T3 and T4 levels should not change when measured due to the expected increase in thyro-globulin binding protein (TBG), however total T4 and T3 are expected to be increased (Rashid & Rashid, 2007). While fluctuations may occur,

13 8 they are not expected to be so great that the values would waiver outside of reference ranges (Casey & Leveno 2006). In a hypothyroid mother during pregnancy, TSH levels are increased with subsequent decreases in free T4 and T3 (Rashid & Rashid 2007). The decreases in free T3 and T4may result in adverse pregnancy outcomes depending on the severity of the deficiency. Because the TSH level is the compound altered in both forms of hypothyroidism, it is the recommended form of initial testing for diagnosis of both overt and subclinical forms (Casey et al., 2007). Also, according to the American Association of Clinical Endocrinologists Guidelines, TSH should always be used to establish the diagnosis of thyroid dysfunction (Baskin et al., 2002).

14 9 Effects of Hypothyroidism The most common outcomes associated with maternal hypothyroidism discussed are: preterm birth, low birth weight, and abruption. In addition to hypothyroidism, isolated hypothyroxinemia is also thought to negatively affect offspring regarding fetal presentation at birth and infant neurodevelopment. All of these effects can be severe, and in the case of neurodevelopment delays, affect individuals for many years. Each aspect of hypothyroidism has adverse effects on pregnancy, which will be discussed in-depth. Abnormal TSH levels have been linked with fetal death in three separate studies. The first studied individuals with no known thyroid dysfunction and excluded those found to have overt hypothyroidism (Benhadi, Wiersinga, Reitsma, Vrikotte, & Bonsel, 2009). While excluding overt hypothyroidism, the reference range for TSH miu/l was used to define hypothyroidism. The study resulted in a significant relationship between risk of fetal loss and an increased TSH in early pregnancy (p = 0.033). This indicated that healthy women without overt hypothyroidism who exhibited increased TSH levels during pregnancy were more likely for their fetus to die in-utero. The second study analyzed a population subset without excluding any form of hypothyroidism (Allan et al., 2000). The study analyzed women with TSH values greater than or equal to 6 miu/l and found there to be a higher rate of pregnancy complications when women had increased TSH levels, specifically that of fetal death (Allan et al., 2000). This trend was observed from the second-trimester onward. Increased TSH levels have also been linked with a risk of very preterm delivery, by approximately three-fold (Stagnaro-Green, Chen, Bogden, Davies, & Scholl, 2005).

15 10 The third study analyzed individuals with TSH values between 2.5 and 5.0 miu/l in the first trimester (Negro et al., 2010). In this study, women were divided into two groups, those with TSH values less than 2.5 miu/l, and those with TSH values between 2.5 and 5.0 miu/l. The study analyzed women originally separated into two groups: those considered high-risk in a selective screening group, and all women in a universal screening group from a prior study subset. Because a wide variety of pregnant individuals were measured, the study accurately represented the average pregnant individual. The women had TSH values measured within the first 11 weeks of pregnancy. In order to ensure proper comparison of the groups, the authors ensured there was no difference in mean gestational week of the initial visit between the two. The study found a significantly higher rate of spontaneous pregnancy loss in those with higher TSH concentration (p = 0.006). Recently, upon examining otherwise healthy pregnant individuals, an additional relationship was reported between elevated TSH levels at 36 weeks gestation and breech presentation with no relationship observed at 12 or 24 weeks gestation (Kuppens et al., 2009). An elevated TSH was defined using the universally accepted reference range of miu/l. It was concluded that an elevated TSH at 36 weeks gestation in otherwise healthy women was a predictor for breech presentation at term, and increased the risk of the fetus presenting in a breech position by two and a half times that of an individual with normal TSH levels at 36 weeks gestation (Kuppens et al., 2009). There was no association between breech position and free T4 levels during any trimester. In a study where effects of both subclinical hypothyroidism and isolated hypothyroxinemia on pregnancy outcomes were analyzed, the subclinical form was found to be much more debilitating than the isolated (Casey et al., 2007). Where the isolated form was not

16 11 associated with any adverse outcomes, the subclinical form was linked with increased risk of abruption and preterm birth, as well as increased number of mothers subsequently diagnosed with gestational diabetes mellitus (Casey et al., 2007). Additionally, neonates born to mothers with subclinical hypothyroidism in the first half of pregnancy were found to have an increased likelihood of lower 5-minute APGAR scores, neonatal intensive care admissions, and development of respiratory distress syndrome (Casey et al., 2007). A separate study analyzing the effects of solely subclinical hypothyroidism in the first 20 weeks of gestation found mothers with subclinical hypothyroidism to be three-times more likely to experience placental abruption when compared to normal, euthyroid mothers (Casey et al., 2005). The study also observed a two-fold increased likelihood of preterm birth in those with subclinical hypothyroidism. These outcomes were calculated based on comparing subclinical hypothyroid to euthyroid mothers with similar gestational ages at delivery (Casey et al., 2005). Similar findings were also observed in another study which linked first and second trimester subclinical hypothyroidism with an increased risk of preterm labor as well as macrosomia (Cleary-Goldman et al., 2008). Furthermore, a study performed on children aged 7 to 9 years of age analyzed neuropsychological status in those born to hypothyroid and euthyroid mothers (Haddow et al., 1999). Overt hypothyroidism was analyzed in the study, using TSH concentrations in the highest 98th percentile as an upper limit, although did not state what that limit was numerically. Results were organized and compared using maternal treated hypothyroidism, untreated hypothyroidism, or euthyroidism as domains. Neuropsychological testing assessed intelligence, attention, language, reading ability, school performance, and visual-motor performance. Socioeconomic status, education, and occupation of the mothers were accounted for by pairing individuals from

17 12 respective groups. The original data regarding maternal thyroid status during pregnancy was obtained from a database and therefore this was not a longitudinal study. However upon testing, children of mothers with hypothyroidism performed less well than those of euthyroid mothers on all components. This was statistically significant in 2 of the 15 domains, which were attention (p = 0.01) and language (p = 0.04). Additionally, the average IQ of children born to hypothyroid mothers was 7 points less than that of the euthyroid group (p = 0.005). In regards to treating hypothyroidism during pregnancy, there were larger deficits apparent in the subset of children born to untreated hypothyroid mothers while those of treated mothers had similar scores to that of the euthyroid group. These findings resulted in conclusions that treating hypothyroidism during pregnancy appeared to be beneficial to the child, even if inadequate. There was also a conclusion stating differences in testing may occur between children born to mothers with mild or asymptomatic hypothyroidism and those of euthyroid mothers (Haddow et al., 1999). In addition to the effects of overt and subclinical hypothyroidism, isolated hypothyroxinemia has also been linked with adverse outcomes. One study analyzing both subclinical hypothyroidism and hypothyroxinemia during first and second trimesters found hypothyroxinemia to have more effect (Cleary-Goldman et al., 2008). While the subclinical form was not found to be associated with any effects, hypothyroxinemia was associated with preterm labor and macrosomia when present during the first trimester (Cleary-Goldman et al., 2008). When occurring during the second trimester, a correlation between hypothyroxinemia and the diagnosis of maternal gestational diabetes mellitus was also observed (Cleary-Goldman et al., 2008).

18 13 Hypothyroxinemia has also been suggested to correlate with an abnormal presentation of the fetus at birth (Wijnen et al., 2009). A study analyzing the relationship of free T4 at 36 weeks gestation and fetal position at birth found an inverse relationship between hypothyroxinemia and abnormal presentation. Abnormal presentation was described as any position other than the universally preferred presentation, which is anterior cephalic positioning (Wijnen et al., 2009). While the previous study displayed a link between late gestation hypothyroxinemia and abnormal presentation, an additional association has been formed between early gestation hypothyroxinemia and abnormal presentation, this form being breech. The study ensured overt hypothyroidism would be excluded by using an upper limit of 2 miu/l for TSH values. This study measured thyroid hormone levels at 12, 24, and 32 weeks gestation and correlated with fetal presentation at birth (Pop et al., 2004). The risk of breech position at term was shown to be four-times greater if the mother was in the lowest 10th percentile of free T4 levels at 12 weeks gestation, while subclinical hypothyroidism did not appear to result in an abnormal presentation (Pop et al., 2004). Breech presentation in this study was shown to be independently related to hypothyroxinemia at 12 weeks gestation (Pop et al., 2004). Lastly, the question of a relationship between hypothyroxinemia and developmental delays is one of increasing importance. Several studies have been done regarding the topic at various ages of offspring born to hypothyroid mothers, and all report a variable delay in development of offspring. The oldest study measured development at three weeks of age after continuously monitoring maternal TSH and free T4 levels throughout pregnancy (Kooistra, Crawford, van Baar, Brouwers, & Pop, 2006). The researchers investigated seven separate clusters of development derived from the Neonatal Behavioral Assessment Scale. These clusters were as follows: habituation, orientation, motor, range of state, regulation of state, autonomic

19 14 stability, and reflexes. The writers found a correlation between first trimester maternal hypothyroxinemia and neonatal development scores which were most notable in the orientation cluster of the scoring system (Kooistra et al., 2006). The orientation cluster measured the neonate s abilities to incorporate auditory and visual stimuli, as well as the quality of attachment. There was no relationship between maternal free T4 during the second or third trimesters nor TSH in any trimester and poor development values (Kooistra et al., 2006). When development was assessed at 10 months of age and correlated with maternal free T4 concentrations, there was a significant relationship between free T4 values and psychomotor development (Pop et al., 1999). Maternal free T4 in the lowest 10th percentile at 12 weeks gestation was correlated with low scores on the psychomotor development scale, which represented a one-month delay overall (Pop et al., 1999). This observation was not seen with free T4 levels at 36 weeks gestation (Pop et al., 1999). Overall, lower maternal free T4 resulted in a lower score on the psychomotor exam. Children of mothers with free T4 levels in the lowest 5th and 10th percentiles were also shown to have lower scores on the mental development exam versus those of euthyroid mothers, however the differences were not shown to be statistically significant (Pop et al., 1999). In a randomized three-year follow-up study analyzing developmental outcomes of children born to mothers with hypothyroxinemia, the relationship was again observed between dysfunction in early gestation and developmental delays throughout the first two years of life (Pop et al., 2003). Children of hypothyroxinemic mothers analyzed at one year of age had significant differences when compared to children born to euthyroid mothers under similar circumstances, which were present in both mental and motor scales (Pop et al., 2003). Of the total number of children displaying developmental delays at one year of age born to

20 15 hypothyroxinemic women, 79% were shown to have mental delays and 76% with motor delays (Pop et al., 2003). Additionally, children of hypothyroxinemic mothers tested at the age of two were again shown to have delays in both mental and motor aspects of development (Pop et al., 2003). Regarding the data from two years of age, of all children tested, children of hypothyroxinemic mothers represented 73% displaying mental delays and 77% exhibiting motor delays (Pop et al., 2003). Overall, 52% of children with delayed mental or motor functioning at one year of age were also delayed at two years of age. Because the evaluations were based on a standardized exam, scores at two years of age were known to be indicative of functioning level at five years of age (Pop et al., 2003). These results caused researchers to conclude that early gestational maternal hypothyroxinemia was an independent risk factor for neurodevelopmental delay of offspring (Pop et al., 2003). Further analyzing the effects of maternal hypothyroxinemia, a study researched cognitive function in children of mothers with free T4 levels in the lowest 10th and 5th percentiles at 13 weeks gestation (Henrichs et al., 2010). Women with free T4 levels in the lowest 10th percentile were termed to have mild hypothyroxinemia while women with levels in the lowest 5th percentile were termed to have severe hypothyroxinemia (Henrichs et al., 2010). All women had normal TSH values. The study measured verbal and nonverbal cognitive development at 18 and 30 months. This was done by means of a parental survey using standardized forms. At 18 months, expressive vocabulary was assessed and at 30 months, language development and nonverbal cognitive development was assessed (Henrichs et al., 2010). The study found a decreased risk of expressive delay in those with higher maternal free T4 values at 30 months. This finding correlates with the observation that children of mothers with mild hypothyroxinemia were noted to have nonsignificant language delays at 18 and 30

21 16 months and significant expressive language delays across ages (Henrichs et al., 2010). Additionally, severe hypothyroxinemia was found to predict an increased probability of expressive language delay at 18 and 30 months and across ages, as well as a nonverbal cognitive delay at 30 months (Henrichs et al., 2010). These findings led to the conclusion that early pregnancy TSH levels are not related to cognitive outcomes, and severe hypothyroxinemia was negatively associated with all forms of cognitive functioning in early childhood (Henrichs et al., 2010).

22 17 Treatment Although the American Association of Clinical Endocrinologists state levothyroxine is safe to use in pregnancy and recommend treating overtly hypothyroid mothers (Baskin et al., 2002), the efficacy and demonstration of favorable maternal and fetal outcomes in treatment of subclinical hypothyroidism and hypothyroxinemia has yet to be determined. Several studies have taken hypothyroid mothers and subsequently began treatment once the diagnosis of hypothyroidism was established with favorable outcomes reported. In regards to treatment, efficacy, quantity, and cost are three domains heavily weighted in determining recommendations. In a study comparing euthyroid and hypothyroid mothers at conception and subsequent pregnancy outcomes regarding preterm delivery and abortion rate, it was shown that adequate treatment of hypothyroidism during gestation minimized risk of adverse pregnancy outcomes (Abalovich et al., 2002). According to the study, adequate treatment included detecting hypothyroid state before pregnancy, monitoring TSH and free T4 levels throughout pregnancy, as well as maintaining a euthyroid state (Abalovich et al., 2002). The goal of the treatment throughout the study was to maintain maternal TSH between miu/l throughout pregnancy, which was done by measuring TSH throughout pregnancy at least once per trimester. The study also concluded pregnancy evolution was dependent on treatment received rather than the maternal form of hypothyroidism based on the observation that pregnancy outcomes were not changed by the form of maternal hypothyroidism (Abalovich et al., 2002). A more recent study which analyzed treatment and rates of adverse outcomes also found treatment to result in significant decline in adverse outcomes of low-risk mothers (Negro et al., 2010). The study compared low- and high-risk mothers in relation to thyroid dysfunction as well as universal screening versus case-finding for thyroid disease. All individuals were classified as

23 18 low- or high-risk and then each risk group was separated into case-finding and universal screening. All individuals had thyroid panels at the initial visit, however the low-risk casefinding sera was frozen for testing postpartum. Of the sera tested immediately, the ones found to have hypothyroidism were then treated to maintain a TSH level less than 2.5 miu/l in the first trimester and less than 3 miu/l during the second and third trimesters (Negro et al., 2010). After pregnancy was completed, the low-risk groups were then compared and found 92% of women in the case-finding group had at least one adverse outcome in contrast to 37% of those universally screened (Negro et al., 2010). The adverse outcomes evaluated had previously been associated with thyroid disease during pregnancy, and included but were not limited to, miscarriage, abruption, preterm labor, respiratory distress, NICU admissions, and low birth weight (Negro et al., 2010). Haddow (1999) compared IQ scores in offspring of individuals with undetected hypothyroidism, detected and inadequately treated hypothyroidism, and euthyroidism during pregnancy. As previously discussed, the study tested neuropsychological status and found children of mothers with hypothyroidism had decreased performances in all areas of testing, with significant differences in 2 of the 15 areas tested, which were attention and language (Haddow et al., 1999). Among children displaying decreased testing scores, there were larger deficits noted in those of the untreated subset, while treated children had similar scores to those of the euthyroid subset (Haddow et al., 1999). Based on these findings, it was concluded differences in performance can occur and possibly be significant at any degree of hypothyroidism. Treatment efficacy, even if inadequate, was also indicated to potentially result in performance variants, as displayed in results of neuropsychological testing (Haddow et al., 1999). The study also predicted an increase in

24 19 approximately four IQ points of offspring and reduced morbidity for women who would be identified and treated (Haddow et al., 1999). Because the study analyzed pregnancies after the first trimester of pregnancy, it was suggested thyroid insufficiency beyond the first trimester also has adverse effects (Haddow et al., 1999). Abalovich (2002) found treatment sufficient to maintain a euthyroid state during pregnancy minimizes the risk of abortion. The study also found pregnancy outcomes to be dependent on treatment received rather than the form of hypothyroidism based on the finding that there was no difference in pregnancy outcomes of those with overt or subclinical hypothyroidism (Abalovich et al., 2002). Additionally, when mothers with established thyroid disease were maintained at a euthyroid state throughout pregnancy, no major pregnancy-related problems were observed (Harborne et al., 2005). It has also been suggested the possibility that adequate treatment throughout pregnancy, with dose-adjustment when necessary may reduce the probability of having an adverse pregnancy outcome traditionally associated with hypothyroidism, such as cesarean section rates, pre-eclampsia, neonatal unit admissions, neonatal weight, and gestational age at delivery (Idris, Srinivasan, Simm, & Page, 2005). Successful treatment of overtly hypothyroid mothers throughout pregnancy requires maintenance of a euthyroid state (Committee on Patient Safety and Quality Improvement & Committee on Professional Liability, 2007). This is done by monitoring thyroid levels throughout gestation and determining the required dose. It is currently recommended by the American Association of Clinical Endocrinologists to assess serum TSH levels every 6 weeks during pregnancy (Baskin et al., 2002).

25 20 While it remains debatable to treat subclinical hypothyroidism and hypothyroxinemia, there is a known advantage to treating overtly hypothyroid mothers to prevent adverse pregnancy outcomes. Additionally, the information used to treat hypothyroid mothers overall will be useful if treatment of subclinical hypothyroidism and hypothyroxinemia were to be recommended in the future. In a recent study determining frequency of elevated TSH in the first trimester within lowrisk individuals where thyroid dysfunction would otherwise be undiagnosed, the frequency was 0.25%, 1.2%, and 5.5% using upper limit TSH values of 4, 3, and 2.5 miu/l, respectively (Rosario & Purisch, 2010). Due to the predictable decrease in TSH during early pregnancy, requirements of levothyroxine treatment to maintain a state of euthyroidism throughout pregnancy in mothers with primary hypothyroidism were analyzed and found to also result in a predictable increased demand during early gestation, specifically between six and sixteen weeks (Alexander et al., 2004). Increased dosages of 28% to 48% greater than baseline were required to maintain a euthyroid state throughout pregnancy (Alexander et al., 2004). This is supported by another study which analyzed women with prior diagnoses of hypothyroidism and their subsequent need of levothyroxine dose modification throughout pregnancy (Neto et al., 2007). TSH and free T4 levels were measured every 6 weeks throughout pregnancy, with a treatment goal of TSH between miu/l, and free T4 within the upper one-third of the normal reference interval. The study found 62.5% of hypothyroid subjects required an increase in levothyroxine during the first half of pregnancy (Neto et al., 2007). Thyroid hormone requirements have been shown to require increased monitoring throughout pregnancy. The need for close monitoring and levothyroxine dose-adjustment has been strongly encouraged in the literature. In a recent study of women with treated

26 21 hypothyroidism desiring pregnancy or newly pregnant, a two-tablet increase in levothyroxine upon the first confirmation of pregnancy resulted in a significant risk reduction of maternal hypothyroidism (Yassa, Marqusee, Fawcett, & Alexander, 2010). With the two-tablet increase of levothyroxine, 85% of patients remained euthyroid throughout the first trimester. The study also demonstrated the efficacy of monitoring thyroid function levels every four weeks versus six weeks from the initiation of dose adjustment through midgestation, as more than 90% of abnormal values were identified (Yassa et al., 2010). Harborne (2005) also analyzed patients with known thyroid disease throughout pregnancy and the medication modifications needed (Harborne et al., 2005). The study resulted in 48% of hypothyroid individuals requiring a change in thyroid medication during pregnancy, 84% of which was an increase in the medication. These medication changes were based on free T4 levels measured each trimester (Harborne et al., 2005).

27 22 Screening Because of hypothyroidism effects previously discussed, the question regarding a need for universal screening of hypothyroidism arises. Although the American College of Obstetrics and Gynecologists currently recommend screening to those individuals considered high-risk, there are many opposing opinions (Committee on Patient Safety and Quality Improvement & Committee on Professional Liability, 2007). The argument for universal screening versus selective case-findings as mentioned is debatable. The term universal screening implies measuring thyroid panels in all pregnant individuals, regardless of risk classification while case-finding refers to measuring panels solely in individuals considered high-risk (Baskin et al., 2002). While it is important to detect thyroid dysfunction in high-risk individuals, it is suggested by selectively screening persons, a large portion would be misdiagnosed (Vaidya et al., 2007). In regards to screening, efficacy, timing, parameters, and cost are heavily weighed when establishing recommendations. Potential benefits to screening are the high specificity of free T4 and TSH levels in detecting thyroid dysfunction, reducing the high incidence of thyroid dysfunction in pregnancy, and preventing fetal brain development delays (Rashid & Rashid, 2007). Conversely, a potential disadvantage found is the notion of maternal anxiety at time of testing and throughout treatment. An additional disadvantage to screening is the fact as referenced in Yassa (2010), an average mother presents between 8 and 12 weeks gestation which is late for hypothyroid women as the majority already have an elevated TSH (Yassa et al., 2010). Vaidya (2007) observed a similar discrepancy in research, noting less than 20% of individuals analyzed in the high-risk population were screened (Vaidya et al., 2007).

28 23 When comparing targeted high-risk case finding and universal screening, approximately one-third of patients with hypothyroidism would be missed (Vaidya et al., 2007). This conclusion was formed after measuring thyroid function in a cohort of women presenting at their initial antenatal visit, classifying patients as either high or low-risk based on recommendations, and determining the percent of missed diagnoses (Vaidya et al., 2007). The study found 2.6% of mothers overall had hypothyroidism, with 44.9% of those individuals belonging to the low-risk group which would not have been tested for thyroid dysfunction (Vaidya et al., 2007). In a recent study comparing case-finding and universal screening for thyroid dysfunction, screening did not show a significant benefit to low-risk women in preventing adverse outcomes (Negro et al., 2010). The study divided individuals into universal screening or targeted casefinding groups, then classified individuals as either high or low-risk and compared detection rates as well as adverse outcomes. The study found approximately 36 women would need to be screened in order to detect one individual with a thyroid dysfunction (Negro et al., 2010). However, a more recent study had much different results than the prior study by Negro (2010). Horacek (2010) also compared high-risk case finding to universal screening. The study analyzed individuals in their 9 th to 11 th gestational week and used a TSH upper limit cutoff of 3.5 miu/l (Horacek et al., 2010). In these women, those who would have been considered high-risk were identified. Of the universally accepted risk factors indicating a need to screen, 55% of individuals screened did not have a single risk factor. The researchers therefore concluded that 55% of those with thyroid dysfunction would have been missed (Horacek et al., 2010). Although both TSH and the presence of autoimmune thyroiditis were included in percentages of individuals with thyroid dysfunction who would have been missed if targeted-high risk case finding were utilized to screen, the results remain significant.

29 24 The timing of screening is also an area of debate. Several studies have implicated hypothyroidism occurring specifically during the first trimester is of great concern due to the allegations of causing developmental delays in offspring, and therefore screening should be implemented before or early-on in pregnancy. It has also been shown that early in pregnancy; the fetus is entirely dependent on maternal thyroid hormone levels because it has yet to make its own endogenous supply (Casey & Leveno 2006). This period of time directly correlates with the interval in which thyroid hormones are most important to fetal brain development (Casey & Leveno 2006). It has been concurrently suggested that examining first trimester TSH values is a basic requirement to detect thyroid dysfunction (Springer, Zima, & Limanova, 2009). While it is necessary to have reference ranges in determining the presence of thyroid dysfunction, there is evidence to suggest the reference ranges of non-pregnant individuals may not be accurate due to the physiologic changes in pregnancy related to TSH (Dashe et al., 2005). In an additional study, TSH suppression in pregnancy due to hcg had a predictable effect on reference ranges and therefore called for trimester-specific reference intervals to better detect maternal hypothyroidism (Dashe et al., 2005). This may affect the efficacy of diagnosing individuals with a thyroid dysfunction and therefore prevent appropriate management of dysfunction, as physiologic changes are a known cause of misdiagnosing subclinical hypothyroidism (Dashe et al., 2005). Supporting the belief reference ranges provided by manufacturers are not representative of the pregnant population are numerous studies establishing gestation-specific reference ranges of pregnant individuals throughout the world. The current accepted reference range of TSH according to the American Association of Clinical Endocrinologists is miu/l (Baskin et al., 2002). Several studies formulated gestational age-specific reference intervals within the

30 25 populations studied, and all displayed a disparity between the reference intervals provided for non-pregnant versus pregnant individuals. One specific study not only developed gestational age-specific reference intervals, but also evaluated potential for misdiagnosis by TSH value as well as trimester (Stricker et al., 2007). Misclassification potential was defined as falsely diagnosing an individual with a thyroid dysfunction or incorrectly diagnosing an individual as euthyroid. This was performed by comparing the manufacturer s reference range to a calculated gestational age-specific reference range from the study participants (Stricker et al., 2007). The reference ranges were calculated using 2.5% and 97.5% confidence intervals, expressed in miu/l, and are as follows: first trimester, second trimester, and for the third trimester (Stricker et al., 2007) When comparing gestational age-specific reference ranges to those of non-pregnant individuals, the differences were found to be statistically significant (Stricker et al., 2007). The writers noted the potential for TSH misclassification was greatest in the first trimester and the potential for free T4 misclassification to be greatest in the second trimester with a range of % misclassification. It was also observed 3.6% of individuals with an elevated TSH would not have been detected (Stricker et al., 2007). The study concluded that accurate diagnosis of thyroid dysfunction in pregnant individuals requires the use of gestation age-specific reference intervals. The notion of a need for specific reference intervals is further supported by a study with the conclusion that applying conventional TSH reference intervals during the first trimester of pregnancy in order to determine a diagnosis of subclinical hypothyroidism resulted in misclassification of greater than 20% of patients (Gilbert et al., 2008). The study also calculated

31 26 reference ranges using 2.5% and 97.5% confidence intervals, and obtained a first trimester reference range of miu/l (Gilbert et al., 2008). One study found free T4 levels to be significantly lower with a narrower distribution most notable during the first trimester while TSH values had a higher and more broad distribution (Cotzias, Wong, Taylor, Seed, & Girling, 2008). The study calculated reference intervals using 2.5% and 97.5% confidence intervals for each week of pregnancy starting at the 6th week, with resulting reference ranges for each trimester. First, second, and trimester TSH values were as follows: miu/l, miu/l, and miu/l, respectively (Cotzias et al., 2008). These findings led to the conclusion that reference intervals have clinical implications regarding hypothyroidism during pregnancy (Cotzias et al., 2008). Dashe (2005) found TSH to be decreased during the first trimester upon forming a reference range throughout the course of pregnancy, indicating an increased need for reference intervals beginning early in gestation. The study formed reference ranges using 2.5% and 97.5% confidence intervals, the reference ranges were expressed in miu/l, and are as follows: first trimester, second trimester, and third trimester. In this study, it was found approximately 28% of those with elevated TSH would not have been identified using traditional reference ranges, contributing to 11% of misdiagnosed euthyroid individuals (Dashe et al., 2005). Contributing to the argument of gestation age-specific reference intervals, Haddow (2004) also studied reference intervals regarding TSH as well as within-person variability of those levels. It was found that TSH had collectively higher values in the second trimester versus the first (Haddow, Knight, Palomaki, McClain, & Pulkkinen, 2004). Reference intervals were created using 95% confidence intervals, and expressed in miu/l. Values calculated were 0.10-

32 for the first trimester and for the second (Haddow et al., 2004). The study also found 70% of the individuals displaying elevated TSH levels in the second trimester were also elevated during the first, indicating a high correlation between trimester thyroid panels (Haddow et al., 2004). This observation may indicate the need for screening during early gestation because there is a high probability of an individual continuing to display elevated TSH levels throughout a pregnancy. A study done by Lambert-Messerlian (2008) also calculated first and second trimester reference intervals as well as within-woman correlations for thyroid function tests. The reference intervals were based on 98% confidence intervals with conversion to multiples of the mean. The intervals themselves were not listed, however upper limits of TSH were 3.95 miu/l for the first trimester and 3.06 miu/l for the second (Lambert-Messerlian et al., 2008) The study observed lower average TSH scores in the first trimester when compared to the second, as well as high correlations of within-woman TSH values in each trimester analyzed (Lambert- Messerlian et al., 2008). Regarding validity of thyroid hormone reference intervals and the applicability towards the general United States population, La ulu and Roberts (2007) calculated and analyzed reference intervals for each of four more common ethnicities in the United States. The study found the majority of reference intervals did not show differences between ethnicities, leading researchers to conclude ethnicity may not be a factor when evaluating thyroid status during pregnancy (La'ulu & Roberts, 2007). Additionally, it was noted the reference intervals calculated were significantly different than those reported by the manufacturer based on the general population. This lead La ulu and Roberts (2007) to conclude the application of reference intervals in pregnant individuals has a potential to misclassify those with thyroid dysfunction and

33 28 in order to accurately classify an individual with thyroid dysfunction during pregnancy, gestational age-specific reference ranges should be utilized (La'ulu & Roberts, 2007). The question of cost is traditionally one heavily weighed when determining recommendations. All laboratories when processing TSH and free T4 panels use CPT codes in order to bill for the service provided. These codes correlate with the cost of a given laboratory value. Each laboratory contracts with insurance companies and negotiates what amount will be reimbursed based on recommendations and standards of care (Green & Rowell, 2008). Upon referencing the Physician s Fee Reference, TSH is estimated to range from $46 - $77, and free T4 to range from $54 - $83. However, upon contacting the Mayo Clinic Laboratory and having a telephone conversation with a technician on August 20 th 2010, the cost for an uninsured individual may have a greater range than expected. At the Mayo Clinic, an uninsured individual would be billed $ for TSH and $ for free T4. A thyroid panel of TSH and free T4 would then maximally cost $ to an uninsured individual. A study done by Thung (2009) investigated the cost of base screening as well as an estimated cost related to an Intelligence Quotient of less than 70, which has been deemed by research to be the mean Intelligence Quotient of an infant born to a hypothyroid mother. The study found for every 100,000 women screened, it would lead to 197 fewer cases of offspring with an IQ less than 85 and therefore a total savings of $8,356,383 healthcare dollars (Thung, Funai, & Grobman, 2009). These numbers reflect an ideal situation of detecting and diagnosing all hypothyroid women during pregnancy. Therefore the study also examined cost if hypothyroidism prevalence was decreased to 0.25% and found there to be an amount of $21,664 gained. Although cost-effectiveness depends on the degree of which treatment adequately reduces the probability of having a child with a lower IQ score, the study showed screening