Clinical Aspects of Hyperthyroidism,

Hypothyroidism, and Thyroid Screening in

Pregnancy

Roberto Negro, MD, FACE, Alex Stagnaro-Green, MD, MHPE

Endocr Pract. 2014;20(6):597-607.

American Association of Clinical Endocrinologists

Abstract and Introduction

Abstract

Objective: To evaluate the peer-reviewed literature on hypothyroidism, hyperthyroidism, and

thyroid autoimmunity in pregnancy.

Methods: We review published studies on thyroid autoimmunity and dysfunction in pregnancy, the

impact of thyroid disease on pregnancy, and discuss implications for screening.

Results: Overt hyperthyroidism and hypothyroidism are responsible for adverse obstetric and

neonatal events. Several studies of association suggest that either subclinical hypothyroidism or

thyroid autoimmunity increase the risk of complications. One randomized controlled trial showed

that pregnant women with subclinical hypothyroidism benefit from treatment in terms of obstetric

and neonatal complications, whereas another study demonstrated no benefit in the intelligence

quotient of babies born to women with subclinical hypothyroidism. Thyroid autoimmunity has been

associated with increased rate of pregnancy loss, recurrent miscarriage, and preterm delivery.

Conclusion: Current guidelines agree that overt hyperthyroidism and hypothyroidism need to be

promptly treated and that as potential benefits outweigh potential harm, subclinical hypothyroidism

also requires substitutive treatment. The chance that women with thyroid autoimmunity may benefit

from levothyroxine treatment to improve obstetric outcome is intriguing, but adequately powered

randomized controlled trials are needed. The issue of universal thyroid screening at the beginning of

pregnancy is still a matter of debate, and aggressive case-finding is supported.

Introduction

Thyroid physiology changes significantly during pregnancy. The metabolic changes include an

increase in iodine renal clearance, the impact of human chorionic gonadotrophin (hCG) on the

thyrotrope receptor, an increase in serum thyroxine-binding globulin (TBG), and inner-ring

deiodination of triiodothyronine (T3) and thyroxine (T4) by the placenta.[1] In geographic areas with

sufficient daily iodine intake, the most significant change in maternal thyroid economy is the

thyrotropic stimulatory action exerted by hCG. The inverse relationship of hCG and

thyroidstimulating hormone (TSH) levels during early pregnancy has been extensively documented

and is particularly evident in the subgroup of women with TSH values in the lower percentiles.[2]

The thyrotropic action exerted by hCG is heightened in multiple-gestation pregnancies, in which

higher hCG levels induce a greater downward shift in TSH levels than is seen in singleton

pregnancies.[3] As a consequence of the first-trimester rise in hCG, a slight and temporary increase

in free (F)T4, total T4, and total T3 levels may be observed. The above-mentioned physiologic

changes induce variations in maternal TSH (lowered) and FT4 (increased), especially during the

first trimester, such that ranges used for the nonpregnant population cannot be applied to the

pregnant state.[4]

Methods

The authors created a list of all relevant topics related to thyroid disease in pregnancy and then

performed a comprehensive literature review, carrying out a systematic PubMed and Medline

search for original articles, review articles, and guidelines published from 1990 through October

2013. Primary papers published prior to 1990 that were seminal in the field were also analyzed. The

search terms used were "thyroid," "levothyroxine" (LT4), "methimazole," "propylthiouracil,"

"TSH," "pregnancy," "hypothyroidism," "hyperthyroidism," "adverse effects," "abortion,"

"miscarriage," "iodine," "thyroid antibodies," and "Hashimoto's thyroiditis." The present manuscript

was constructed based on the best scientific evidence and the skills of the authors.

Results

TSH Trimester-Specific Reference Range

Large-scale studies, developed in iodine-replete populations, have reported median TSH levels of

between 0.8 and 1.1 , 1.1 to 1.3, and 1.2 to 1.4 mIU/L in the first, second, and third trimesters,

respectively.[5–10] Based on these studies, both the American Thyroid Association (ATA) and the

Endocrine Society (ES) guidelines on thyroid and pregnancy have established the upper limit of

TSH at 2.5, 3.0, and 3.0 to 3.5 mIU/L in the first, second, and third trimesters, respectively.

Concurrently, the lower limit considered as normal in the first, second, and third trimesters is 0.1,

0.2, and 0.3 mIU/L, respectively.[11,12] As almost 20% of pregnant women have a normal

physiologic suppression of TSH in the first trimester, it has been questioned whether a lower TSH

limit in the first trimester can truly be defined. As the normal reference ranges in pregnancy are

trimester-specific, the erroneous application of nonpregnant reference range results in an

overestimation of the number of patients classified as "hyperthyroid" and an underestimation of the

number of patients classified as "hypothyroid." This could result in the initiation of antithyroid

drugs (ATDs) in euthyroid women and the withholding of therapy in pregnant women with

subclinical hypothyroidism (SCH), resulting in potential adverse effects on both the mother and

fetus. Given the physiologic changes discussed, it is not unusual to encounter a healthy pregnant

woman with a high-normal FT4 level associated with low-suppressed TSH.[13] This condition is

consistent with the normal physiologic changes that occur during pregnancy and is not associated

with adverse outcomes and does not require treatment.

Discussion

Gestational Transient Thyrotoxicosis

Excessive stimulation induced by elevated hCG concentrations (at least higher than 200,000 IU/L)

may lead to a condition called "gestational transient thyrotoxicosis" (GTT).[14] This condition is

diagnosed in 1 to 3% of all pregnancies and is similar biochemically to Graves disease in that a state

of thyrotoxicosis exists (elevated FT4 and suppressed TSH), but the condition does not exhibit TSH

receptor antibodies (TRAbs), goiter, abnormal thyroid texture on ultrasound, or the presence of

ophthalmopathy. GTT presents in the first trimester of pregnancy at the time of peak levels of hCG

occur. The severity of GTT can vary from morning sickness to hyperemesis gravidarum. Symptoms

of hyperemesis gravidarum include weight loss (>5% of body weight), dehydration, abnormal liver

tests, and ketonuria and at times requires hospitalization for treatment.[15] An association between

GTT and hyperemesis gravidarum exists, as about 50% of patients with hyperemesis gravidarum

present in a state of thyrotoxicosis.[16] GTT often resolves spontaneously and in parallel with the

decline in hCG levels by midgestation (and therefore coincident with the reduction of its thyroid

stimulatory action). FT4 concentrations tend to progressively decline while TSH values may remain

totally or partially suppressed for several weeks.[17] In 1979, Kauppila et al.[18]reported that women

with hyperemesis gravidarum have higher mean hCG concentrations at 7 to 8 weeks, 9 to 11 weeks,

and 12 to 14 weeks as compared with normal pregnant women of matched gestational age, but they

reported no difference between the mean serum concentration when women were tested at 15 to 20

weeks. The authors suggested a causal relation exists between a high serum hCG concentration and

hyperemesis gravidarum. As GTT spontaneously resolves by the end of the first trimester, it does

not require treatment with ATDs, although no prospective study data are available comparing

obstetric outcomes among women receiving treatment and a comparable control group. No benefit

has been reported in the few patients with GTT who were treated with ATDs. It is critical, however,

to differentiate GTT from Graves disease, as only the latter requires treatment with ATDs. As GTT

resolves spontaneously, treatment with ATDs may potentially induce a condition of maternal

hypothyroidism during a critical period for fetal development and viability.

Graves Disease in Pregnancy

Graves disease is the second most frequent cause of hyperthyroidism in pregnancy, with a

prevalence of approximately 0.5%.[19,20] Graves hyperthyroidism usually exacerbates during the first

trimester due to the additive effects of hCG stimulation of the TSH receptor. The disease

ameliorates in the second half of pregnancy as a result of the immunologic remission associated

with pregnancy. Untreated or undertreated hyperthyroidism is associated with an increased rate of

maternal complications (e.g., thyroid storm, gestational hypertension, preeclampsia, miscarriage

and stillbirth, abruptio placentae, preterm delivery [PTD]). The developing fetus may be affected as

well due to both maternal thyrotoxicosis and the passage of TRAbs from the mother to the fetus, so

that it may be useful to check the TRAb titer at approximately 22- to 26-weeks gestation.[21,22]

Fetal complications of uncontrolled hyperthyroidism include intrauterine growth restriction, goiter,

tachycardia, cardiac failure, fetal hydrops, accelerated bone maturation, neurodevelopmental

abnormalities, and low birth weight.[21,22] Retrospective studies demonstrated that the rates of these

complications are significantly reduced by the use of ATDs, namely propylthiouracil (PTU) and

methimazole (MMI).[23,24] The aim of treatment is to maintain FT4 values at, or just above, the

upper limit of normal, while utilizing the smallest possible dose of ATD. In most cases, the dose of

ATDs can be decreased after the first trimester due to the spontaneous remission of the disease. The

rationale for administering the lowest dose of ATDs able to maintain FT4 around the upper limit of

normal is based on two premises: (1) the literature has shown that there are no increased

maternal/fetal adverse effects due to maternal subclinical hyperthyroidism; and (2) maintaining the

lowest maternal dose of ATDs taken by the mother decreases the amount of placental transfer of the

drug(s) to the fetus and therefore decreases the risk of fetal/neonatal hypothyroidism.[25,26]

The last 5 years have witnessed a shift regarding which ATD is recommended during the different

trimesters. PTU administration has been associated with an increased risk of severe liver toxicity

(including during pregnancy), and MMI administration in the first trimester has been associated

with an increased risk of congenital malformations.[27] It should be clearly stated that the risk of

complications in an untreated/undertreated hyperthyroid pregnant woman is clearly higher and more

serious than the potential adverse events associated with the use of ATDs, and as a consequence,

treatment in Graves hyperthyroidism is mandatory[28] Although PTU has been associated with

congenital malformations (situs inversus and/or dextrocardia, isolated unilateral kidney

a/dysgenesis, and cardiac outflow tract defects), these malformations occur singly. In contrast, the

use of MMI seems to be characterized by the presence of an association of malformations, a

specific syndrome called "MMI embryopathy," which includes choanal or esophageal atresia

omphalocele, scalp defects, and dysmorphic facies.[29,30] Consequently, both the ATA and ES

thyroid and pregnancy guidelines recommend the use of PTU in the first trimester and MMI in the

second and the third trimesters.[11,12] However, the risk of switching from PTU to MMI at the

beginning of the second trimester is unknown. The two ATDs display different pharmacokinetics,

have different properties, and different dose ranges. No study has evaluated the bioequivalence

between the two compounds. It can be hypothesized that switching from one ATD to another could

result in a period of uncontrolled hyperthyroidism, with potential detrimental effects[31] The risks of

malformation associated with MMI and of liver failure associated with PTU are definite, although

small, whereas the risks associated with switching ATDs are unknown. Cooper and Rivkes[32]

published an editorial in the Journal of Clinical Endocrinology and Metabolism in which they

recommended that "…treatment with radioactive iodine or surgery before pregnancy should be

strongly considered for those who desire future pregnancy. Doing so can avoid the dilemma of

choosing between a drug associated with a small risk of fetal birth defects and another drug

associated with a similarly small but finite risk of serious liver injury in the mother." Another

potential reason to consider the above-mentioned opinion relates to the possibility of a Graves

relapse during the postpartum period in women who were in remission prior to pregnancy. An

Italian study demonstrated that relapse of hyperthyroidism occurs in 84% of women who have a

pregnancy and that in the vast majority (95.2%), the relapse of Graves hyperthyroidism occurs

between 4 and 8 months after delivery.[33] Nevertheless, there are no studies demonstrating that

surgery or radioactive iodine (RAI) treatment of Graves disease prior to pregnancy results in

improved maternal/fetal outcomes, and women undergoing RAI treatment should defer pregnancy

for 6 months after treatment.

Finally, it should be noted that the postpartum period appears to be a time of increased risk for the

development of de novo Graves disease. Data show that up to 45% of women in the childbearing

years who develop Graves disease are initially diagnosed in the postpartum period, a time of

immunologic flare following the immunosuppression associated with pregnancy. The risk of

women developing postpregnancy Graves disease is greatest in older patients.[34–37]

Hypothyroidism

As noted earlier, pregnancy places unique demands on the thyroid. Specifically, production of T4

and T3 increases by approximately 50% to maintain the euthyroid state. Although this is easily

accomplished in the vast majority of women, those individuals who have decreased thyroidal

reserve, most frequently due to autoimmune thyroid disease, may lack the ability to meet the

increased demand. In this regard, pregnancy should be seen as a stress test for the thyroid,[38] with

pregnancy bringing out the decreased reserve capacity, which is not apparent in the nonpregnant

state.

The prevalence of overt hypothyroidism (OH) first detected during pregnancy ranges from 0.2 to

1.0%.[39] This number appears to be constant over time as well as in different regions of the globe.

For example, the most recent study, published online on July 11, 2013, and which reported the

results of a national survey in Belgium assessing the prevalence of thyroid disorders in 55 obstetric

clinics, reported an OH prevalence of 0.4%.[40] Another way to look at the prevalence data is that

between 1 in 100 to 1 in 500 pregnant women will have undiagnosed OH.

The literature on SCH first detected during pregnancy is notable for the marked changes in

prevalence that have been reported over the last 5 years. Historically, it had been accepted for

decades that the prevalence of SCH during pregnancy hovered between 2 and 3%. Recent research

however has redefined the normal range of TSH during pregnancy to an upper limit of 2.5 mIU/L in

the first trimester and 3.0 to 3.5 mIU/L in the second and third trimesters.[12,21] This redefinition has

resulted in a dramatic increase in the percentage of women classified as having SCH. Utilizing the

new criteria, the Belgian study of 55 obstetric clinics reported an SCH prevalence of 6.8%.[40] Even

more dramatic were the results of a 2012 study that screened 117,892 American women for thyroid

disease during pregnancy.[41] Over 15% (18,291 of 117,892) of the women met the new criteria for

SCH.

It is important to recall that both the ATA and ES guidelines recommend utilizing, when possible,

trimester-specific TSH ranges derived by the population that the test is being utilized for. Korevaar

et al[42] recently published results from a population study of 2,765 Dutch, 450 Surinamese, 308

Moroccan, and 421 Turkish women during pregnancy. Turkish and Dutch women had higher mean

TSH levels during pregnancy than Surinamese and Moroccan women. Interestingly, the percentage

of TRAbnegative women with TSH levels above 2.5 mIU/L in the first trimester was higher in

Dutch (12.0%) and Surinamese women (13.6%) than in Turkish (9.5%) and Moroccan (3.0%)

women.

Maternal and Fetal Impact of OH—Implications for Treatment

In total, 6 studies have evaluated the impact of OH on the mother and fetus.[12,39] Five of the studies

were retrospective, with a single prospective study performed by Sahu et al[43] in 2010. Each of the

studies reported an increase in maternal and fetal adverse outcomes. Maternal complications

reported included preeclampsia, increased placental weight, and gestational hypertension. Fetal

adverse events were more numerous and ranged from spontaneous abortion and fetal death to

cretinism, low birth weight, intrauterine growth retardation, and gestational hypertension. Given the

clear association between OH and negative maternal and fetal outcomes, it is well accepted that OH

must be treated during pregnancy.

Maternal and Fetal Impact of SCH—Implications for Treatment

Numerous studies have evaluated the impact of SCH on the mother and fetus. Although the

majority of studies have demonstrated that SCH has adverse maternal and fetal effects, there have

been studies which have not demonstrated any negative consequences. Negative outcomes reported

include miscarriage, PTD, fetal death, preeclampsia, sepsis, respiratory distress syndrome,

gestational diabetes, gestational hypertension, and decreased intelligence quotient (IQ) in the

offspring. Subsequent pregnancy in women with SCH identified in an earlier pregnancy has been

associated with a significant increase in diabetes and stillbirth as compared with women who were

euthyroid in the initial pregnancy.[44]

Interpreting the literature on SCH and its impact on pregnancy has been muddied by the fact that

most studies utilized an upper limit for TSH of between 4 and 5 mIU/L, which is different than the

now widely accepted upper limit of 2.5 mIU/L. In this regard, 2 studies are of particular interest. In

a 2009 study of 2,497 pregnant Dutch women, Benhadi et al[45] reported a 60% increase in the rate

of child loss for each doubling of TSH level within the normal range.[45] Similarly, in a prospective

trial published in 2010, Negro et al[46] found that of 4,123 Italian TRAb-negative women in the first

trimester of pregnancy, those with a TSH level between 2.5 and 5.0 mIU/L had a 60% increase in

miscarriage rate as compared with women whose TSH level was ≤2.5 mIU/L (6.1% vs. 3.6%;

P<.0006).

To date, only 2 studies have evaluated the impact of LT4 intervention in women with SCH. The first

study, performed by Negro et al,[47] was a prospective trial that divided 4,562 pregnant women into

2 groups. In the universal screening group, all women had thyroid function and thyroid peroxidase

antibody tests performed in the first trimester. In the case-finding group, only women who had risk

factors for thyroid disease (high-risk subgroup) were screened. The low-risk women in the case-

finding group had thyroid function and thyroid peroxidase antibody testing performed postpartum.

All women screened during pregnancy who had a TSH level >2.5 mIU/L and who were thyroid

peroxidase antibody–positive were treated with LT4 during pregnancy. The major outcome variable

was the number of women who had at least one maternal or neonatal adverse outcome. A

significant increase in adverse events was reported in women with SCH who were identified

postpartum and therefore not treated during pregnancy as compared with women with SCH who

were identified and treated during pregnancy. The second study, published by Lazarus et al,[48]

reported the results of a prospective trial that explored how treating pregnant women with SCH

and/or isolated hypothyroxinemia impacts the IQ of their children. The study, performed in the

United Kingdom and northern Italy, compared the IQ of the offspring at 3 years of age of 390

pregnant women with SCH and/or isolated hypothyroxinemia who were treated during pregnancy to

the IQ of the offspring of 404 women with untreated SCH and/or SCH. The median gestational age

of the women who were treated was 13 weeks and 3 days. There were no differences between the

two groups in mean IQ or the percentage of children with an IQ below 85. It is worthy of note that

the median gestational age of initiation of therapy was at the end of the first trimester and therefore

after the critical stage of neurologic development.

In conclusion, the majority of data have demonstrated an association between SCH and

maternal/fetal adverse effects. However, only 2 prospective intervention trials have been published,

and they have yielded mixed results.

Treatment During Pregnancy in Women on LT4 Preconception

During pregnancy, T4 production increases by 20 to 50% in response to elevated levels of TBG.

Women with a normal thyroid gland respond accordingly, and a euthyroid state is maintained

throughout gestation. However, individuals on LT4 prior to pregnancy, either due to autoimmune

thyroid disease, radioiodine ablation, or surgery typically require an increase in the dose of LT4 to

avoid the development of hypothyroidism during pregnancy. Alexander et al[49] demonstrated that

most women will need to increase the dose of LT4 by approximately 50%. The increased need

occurs early in the first trimester and typically plateaus at around 20 weeks. One method of

accomplishing this is to instruct each patient to increase her preconception dose of LT4 by 2 tablets

per week once pregnancy is confirmed.[50] Another possibility is to adjust the dose of LT4

prepregnancy to achieve a TSH level of approximately 1.0 mIU/L. Abalovich et al[51] demonstrated

that the majority of women who have a TSH level <1.2 mIU/L preconception do not need to

increase their dose of LT4 during pregnancy. Postpartum, the majority of women will return to their

preconception dose. However, women on LT4 secondary to Hashimoto's thyroiditis preconception

who still have functioning thyroid tissue may develop postpartum thyroiditis in the year following

the birth of their child.[52]

Thyroid Antibodies in Pregnancy

Thyroid Antibodies in Unselected Pregnancies and Fetal Loss. Thyroid autoimmunity is not

uncommon among women of reproductive age. Thyroid autoantibodies are found in 5 to 15% of

women of reproductive age, and thyroid autoimmunity has been associated with adverse pregnancy

outcomes, independent of thyroid dysfunction.[21] In 1990, Stagnaro-Green et al[53] published the

first paper showing a positive association between autoimmunity and miscarriage. Specifically,

euthyroid women with thyroid antibodies had a 2-fold increase in the risk of miscarriage (17% vs.

8.4%).[53] Since the publication of that study, multiple studies have addressed this issue, with the

vast majority confirming the initial findings. Iijima et al[54] also reported a 2-fold increase in the rate

of miscarriage in women with thyroid autoimmunity, and in a study involving 1,500 patients,

Ghafoor et al[55] found that 36% of women with thyroid antibodies experienced miscarriage versus

1.8% of controls (odds ratio [OR], 31.07; 95% confidence interval [CI], 18.6–51.8). In a small

prospective study, Sezer and colleagues[56] reported no increase in pregnancy loss in women with

thyroid autoantibodies versus women without (28.6% vs. 20%; P = not significant).

Several meta-analyses demonstrated a clear increased risk of miscarriage in women, with a clear

association identified between the presence of thyroid antibodies and miscarriage (e.g., OR, 1.99;

95% CI, 1.42–2.79[57] and OR, 3.90; 95% CI, 2.48–6.12 [58]). Women with thyroid autoimmunity

(TAI) have also been shown to be slightly older and have a higher mean TSH level than women

without TAI (although TSH levels were well within the normal limits for pregnancy in both

groups).

There are 3 hypotheses regarding the link between the presence of thyroid autoantibodies and

spontaneous miscarriage. The first hypothesis is that autoimmunity increases the risk for developing

(sub)clinical hypothyroidism, perhaps most pronounced at the placental level. The second

hypothesis is that thyroid antibodies can be considered an expression of autoimmunity in general

and that the adverse fertility and obstetric outcomes may be caused by a related immune

dysfunction and/or associated general autoimmune disorders. The third hypothesis is that thyroid

antibodies directly impact the pregnancy, leading to pregnancy loss. It is of note that studies

published both in the United States and Israel have demonstrated a decrease in litter size in animal

models of autoimmune thyroid disease.

Thyroid Antibodies in Unselected Pregnancies and PTD

PTD, defined as delivery prior to 37-weeks gestation, occurs in 12% of pregnancies in the United

States and is associated with increased risk of neonatal death and increased medical costs due to

perinatal complications and permanent disability. Thyroid autoimmunity has been associated with

adverse obstetric outcomes, particularly with PTD. The first report of an association between TAI

and PTD was published in 1994 by Glinoer,[59] who prospectively evaluated changes in thyroid

function in 87 Belgian women in the first trimester of pregnancy. In that study, women with TAI

showed a 100% increase in the rate of PTD as compared with controls (8% vs. 16%). Three years

later, Iijima et al[54] evaluated the impact of 7 autoantibodies on pregnancy outcome in 1,200

pregnant women and reported no difference in the incidence of PTD between women with or

without TAI. A recent metaanalysis evaluated 11 prospective cohort studies involving 35,467

participants. The combined relative risk of preterm delivery for pregnant women with thyroid

antibodies compared with the reference group was 1.41 (95% CI, 1.08–1.84; P = .011).[60] Once

again, an explanation for the statistical relationship between TAI and PTD is unknown, with

potential hypotheses including: (1) thyroid autoimmunity implies a reduced functional reserve,

which may predispose to thyroid insufficiency during pregnancy; and (2) thyroid autoimmunity

may be a marker of an unfavorable autoimmune environment in which PTD represents a form of

fetal rejection, analogous to graft-versus-host disease.

Thyroid Antibodies in Women With Recurrent Abortion and Fetal Loss

Recurrent pregnancy loss is defined as 2 or 3 consecutive spontaneous pregnancy losses without a

live intervening birth and occurs in 1 to 3% of all couples trying to conceive. The potential

association between thyroid antibodies and recurrent miscarriage has been investigated by several

authors. The first study was performed in 1996 by Roberts et al,[61] who showed that women with

recurrent miscarriage had a significant increase in both thyroid antibodies and the number of

CD5/CD20-positive cells compared with women with normal pregnancies. One year later, Bussen

and Steck[62] found that the incidence of thyroid antibodies in euthyroid women with recurrent

pregnancy loss was significantly increased compared with controls of reproductive age without

previous abortions. In addition, Kutteh et al[63] examined 700 women with a history of 2 or more

consecutive pregnancy losses and reported a significant increase in the rate of thyroid antibody

positivity in women with recurrent abortion as compared with 200 healthy controls (22.5% vs.

14.5%). A positive association was also found by other authors, and in a case-control study, Iravani

et al[64] reported that patients with primary recurrent pregnancy loss had an increased prevalence of

thyroid antibody positivity compared with controls (OR, 2.24; 95% CI, 1.5–3.3). On the other hand,

Esplin et al[65] and Rushworth[66] demonstrated no difference in thyroid antibody positivity between

patients with recurrent pregnancy loss and healthy controls.

A meta-analysis published in 2011 evaluated the association between thyroid antibodies and

recurrent miscarriage in 8 studies that involved 460 patients with thyroid antibodies and 1,923

antibody-negative controls. The results showed that patients with recurrent miscarriage more often

had thyroid antibodies (OR, 2.3; 95% CI, 1.5–3.5).[57]

A recent study from the United Kingdom analyzed 496 women with unexplained recurrent

miscarriage and 220 women with known diagnoses of recurrent miscarriage.[67] The thyroid

peroxidase antibody (TPOAb) positivity was similar in the 2 groups (10.7% vs. 11.8%,

respectively). Moreover, T4 replacement (50 μg daily during pregnancy) was begun in some patients

who tested positive for TPOAb, irrespective of TSH level, with no difference in live birth rate

between TPOAb (−), TPOAb (+), and TPOAb (+) patients treated with L4. These results led the

authors to conclude that TPOAb-positive status does not have a prognostic value regarding the

outcome of a subsequent pregnancy, and empirical T4 therapy in those who tested positive does not

improve outcome.

In conclusion, there is a positive association between thyroid antibodies and recurrent pregnancy

loss; however, the data are less robust than for sporadic loss and are somewhat contradictory. This

may be because recurrent pregnancy loss has many potential causes, and endocrine dysfunction may

only account for 15 to 20% of all cases. It should be noted that many of the published studies did

not control for other potential etiologies of recurrent losses (chromosomal anomalies, immunologic

derangements, uterine pathology).[68]

Thyroid Antibodies in Women Undergoing In Vitro Fertilization (IVF) and Success Rates

Studies have also evaluated the potential association between thyroid autoimmunity and pregnancy

results in women undergoing IVF. Women undergoing IVF are subfertile by definition, and

multiple factors could potentially affect the outcome of pregnancy, making study of this population

difficult. For example, women undergoing assisted reproduction technologies are usually older than

spontaneously pregnant women, and it is well documented that the prevalence of thyroid

autoimmunity increases with age. It is therefore interesting from a scientific and clinical point of

view to determine whether or not the presence of thyroid autoimmunity may have a negative impact

on IVF success rate in this specific category of patients.

In 1999, Muller et al[69] published a prospective, nested case-control study of 173 subfertile women

undergoing IVF. Pregnancy occurred in 48% of the antibodypositive women and in 28% of the

antibody-negative women (difference not significant). Among those who became pregnant,

miscarriage occurred in 33% (4/12) of TPOAb-positive women and in 19% (8/42) of

TPOAbnegative women, with no significant difference between the 2 groups, probably due to the

small number of subjects investigated. In 2003, Poppe et al[70] evaluated 234 women (14% with

thyroid antibodies) and found no difference in pregnancy rate between women who were antibody-

positive or -negative (53% vs. 43%). However, women with thyroid antibodies miscarried in 53%

of the cases versus 23% of controls (P = .016). A prospective study involving 484 patients

published 2 years later Negro et al[71] found no difference in pregnancy rates but did report a

significant increase in the miscarriage rate in women with thyroid antibodies compared with women

without the antibodies (52.4% vs. 25.8%). Finally, Kilic et al[72] studied 69 patients with idiopathic

infertility in a prospective, cross-sectional study. Patients with thyroid antibodies (who were of

similar age and body mass index as the antibody-negative patients) had a clinical pregnancy rate

that was significantly lower than controls (30.4% vs. 41.9%).

A meta-analysis that included the 4 above-mentioned studies found that subfertile women with TAI

undergoing IVF had a 2-fold increased risk for miscarriage compared with subfertile women

without TAI, but the women in each group had a similar pregnancy rate. These results are in

agreement with those of similar studies on spontaneous pregnancies.[73]

IVF is unique in that ovarian hyperstimulation prior to implementation of assisted reproduction

technology (ART) leads to an increase in estradiol levels, resulting in an increase in TBG and TSH

levels with reduced FT4 levels. In essence, the impact of controlled ovarian hyperstimulation on

thyroid function is to exacerbate the normal demand that pregnancy places on the thyroid. In

women with autoimmune thyroid disease, who already have decreased thyroid reserve as reflected

by their prestimulatory serum TSH and FT4 levels, the hyperstimulation inherent in IVF may lead to

a transient worsening of thyroid status that results in pregnancy loss.[74] In this situation, it is

advisable that serum TSH levels be maintained at least <2.5 mIU/L (as in patients who are on LT4

treatment) and preferably <1.2 mIU/L[51] before starting ovarian stimulation and that thyroid

function be monitored closely thereafter.

Thyroid Antibodies and Pregnancy-Intervention Trials

Multiple studies and meta-analyses have demonstrated that women with thyroid autoimmunity have

an increased risk of miscarriage. To date, few studies investigating the potential benefit of treating

euthyroid antibody-positive women undergoing IVF with LT4 have been published.

Three studies have examined the potential benefit of LT4 intervention in thyroid antibody-positive

women undergoing IVF. The first study, published in 2005 by Negro et al,[71] divided euthyroid

(TSH, 0.27 to 4.2 mIU/L) antibody-positive women into 2 groups. One group was treated with LT4

at a dose of 1 μg/kg of body weight, whereas the second group received a placebo. The study also

included a control group of antibody-negative women. The results showed that there was no

difference in the pregnancy rates between the 3 groups; however, antibody-positive women

miscarried significantly more than antibody-negative women, and women treated with LT4 had a

lower rate of miscarriage compared with the placebo-treated group, although this difference was not

significant, probably due to a limited sample size. In 2010, Abdel Rahman et al[75] divided 70

women with thyroid antibodies (TSH, 0.27 to 4.2 mIU/L) into an intervention group (50 to 100 μg

of LT4) and a placebo group. Their results showed that the group treated with LT4 had a

significantly lower miscarriage rate and higher clinical pregnancy and delivery rates than the

placebo group. In 2011, Kim et al[76] conducted a study in which they divided women with thyroid

antibodies and TSH levels between 0.27 and 4.0 mIU/L into 2 groups, one of which was treated

with LT4 50 μg/day and the other left untreated. No significant difference in the clinical pregnancy

rate per cycle was observed between the 2 groups. However, the miscarriage rate was significantly

lower in the LT4 treatment group compared with the control group. The embryo implantation and

live birth rates were also significantly higher in the LT4 treatment group.[76]

A meta-analysis that pooled data derived from the above-mentioned studies concluded that patients

with thyroid autoimmunity and SCH who undergo ART may benefit from intervention with LT4

supplementation in order to improve fertility and subsequent pregnancy outcomes (delivery).[77]

Another prospective, randomized interventional trial of LT4 in euthyroid spontaneously pregnant

women with thyroid antibodies was published in 2006 by Negro et al.[78] The authors reported a

significant decrease in the rate of pregnancy loss in the treated group (3.5% vs. 13.8%; P<.05). The

limitation of this study was that the mean estimated gestational age when starting LT4 was 10

weeks, and all but one of the losses occurred at less than 11 weeks.

In conclusion, although the possibility that a woman with thyroid autoimmunity may benefit from

LT4 treatment in order to improve obstetric outcome is intriguing, adequately powered randomized

controlled trials are needed before LT4 should be prescribed on a routine basis in such patients.

Iodine in Pregnancy

Iodine is necessary for the production of thyroid hormone but cannot be produced by the body.

Therefore, iodine must be ingested, either as a component of the diet or through dietary

supplements. During pregnancy, the need for iodine increases by approximately 50% due to the

maternal need to produce more thyroid hormone, enhanced renal losses secondary to the increased

glomerular filtration rate seen in pregnancy, and the fetal need to produce thyroid hormone during

the second half of pregnancy. Increase maternal iodine intake is also necessary during lactation, as

this serves as the sole source of iodine in the newborn.

The central role maternal iodine status plays in development of childhood cognition was clearly

confirmed in the Avon Longitudinal Study of Parents and Children.[79] In this British study, IQ at

age 8 years (Wechsler Intelligence Scale for Children) and reading speed, accuracy, and

comprehension (Neale Analysis of Reading Ability) at age 9 years were assessed in 7,408 children.

In the respective mothers, urinary iodine concentration was measured in stored samples from the

first trimester (≤13 weeks gestation; median, 10 weeks). Iodine to creatinine ratios were

dichotomized to <150 μg/g or ≥150 μg/g on the basis of World Health Organization criteria for

iodine deficiency or sufficiency in pregnancy. The results showed that after adjustment for

confounders, children of women with an iodine to creatinine ratio of <150 μg/g were more likely to

have scores in the lowest quartile for verbal IQ, reading accuracy, and reading comprehension than

children of mothers with ratios ≥150 μg/g. Moreover, when the <150 μg/g group was subdivided,

scores worsened progressively in the ≥150 μg/g, 50 to 150 μg/g, and <50 μg/g subgroups. The

above-mentioned data highlight the importance of adequate iodine status during early gestation and

emphasize the risk of iodine deficiency even in developed countries and the need for randomized,

placebo-controlled trials to test the effect of maternal iodine supplementation on child cognition.

Data from the National Health and Nutrition Examination Survey (NHANES) has documented a

marked decrease in the median urinary iodine concentration (MUIC) over the last 3 decades. The

Institute of Medicine recommended dietary allowance for iodine during pregnancy is 220 μg and

290 μg for lactation.[80] NHANES data published in 2012 revealed that the MUIC for pregnant

women was 125 μg/L, indicating that pregnant women in the United States are probably mildly

iodine deficient.[81] Consequently, multiple organizations, including the ATA, the ES, the American

Association of Clinical Endocrinologists, and the Teratology Society recommend that all pregnant

and breast-feeding women take a prenatal vitamin that contains 150 μg of potassium iodide.[82]

Thyroid Screening in Pregnancy

As data continue to emerge linking thyroid abnormalities with adverse maternal and fetal outcomes,

the debate regarding the pros and cons of universal screening for thyroid disease during pregnancy

has intensified. Whether or not a society decides to screen for thyroid disease during pregnancy

depends on answers to the following questions: (1) is thyroid disease common during pregnancy?;

(2) does thyroid disease during pregnancy have adverse maternal and fetal effects?; (3) is there a

safe, inexpensive, and universally available methodology available to perform thyroid screening?;

(4) once women with thyroid disease in pregnancy are identified, does therapeutic interventions

exist which will decrease the rate of the adverse maternal/fetal effects caused by the thyroid

disease?; and (5) is screening and intervention to decrease the maternal/fetal adverse outcomes cost-

effective?

Clearly, thyroid disease during pregnancy is common, is associated with adverse maternal/fetal

outcomes, and a screening method that is inexpensive and available exists. Overt hyperthyroidism

occurs in approximately 0.5% of women, whereas OH occurs in 0.2 to 1.0% of pregnant women.

SCH occurs in up to 15% of women, and thyroid antibodies are present in between 10 and 20% of

all pregnant women. Overt hyperthyroidism and OH have well-defined adverse maternal/fetal

effects. The majority of published studies have also demonstrated a significant association between

SCH and negative fetal and maternal outcomes. Screening for TSH level followed by a reflex free

T4 if the TSH is abnormal is safe, cheap, and readily accessible. TPOAb testing is also inexpensive,

reliable, and easily obtained.

It is well accepted that treating OH and overt hyperthyroidism decreases maternal and fetal

complications. However, there have been only 3 studies assessing the impact of treating SCH

during pregnancy. Two studies documented a positive impact, with the first study demonstrating a

marked decrease in the incidence of miscarriage and PTD in thyroid peroxidase antibody-positive

women and the second study showing a decrease in overall maternal/fetal events in thyroid

peroxidase antibody-positive women with a TSH level that exceeds 2.5 mIU/L. The third study

reported no impact on the IQ of the children of mothers with SCH who were treated with LT4

during pregnancy. Until the outcomes of studies in this area currently being conducted in the United

States, United Kingdom, and China are completed, it must be concluded that the data are too

preliminary to make a determination on maternal/fetal adverse events associated with LT4 therapy

during pregnancy in women with SCH.

Based on data presented above, the ATA[12] and the ES[11] have published clinical guidelines on

thyroid and pregnancy, including recommendations on universal screening. The ATA guidelines,

published in 2011, stated that "There is insufficient evidence to recommend for or against universal

TSH screening at the first trimester visit." Instead, the ATA recommended screening all women

who are at high risk for thyroid dysfunction during pregnancy. The ES clinical guidelines

committee did not reach consensus on the screening issue and therefore issued 2 recommendations:

"Some members recommended screening of all pregnant women for serum TSH abnormalities by

the ninth week or at the time of their first visit," whereas "Some members recommended neither for

nor against universal screening of all pregnant women for TSH abnormalities at their first visit.

These members strongly support aggressive case finding to identify and test high-risk women…"

In 2012, after both the ES and ATA guidelines were completed, an analysis of the cost-

effectiveness of universal screening for thyroid disease in pregnancy versus screening high-risk

women versus no screening was published by Dosiou et al.[83] A decision-analytical model indicated

that universal screening and high-risk screening were costeffective compared with no screening.

Given the uncertainty regarding the impact of treating SCH on decreasing the rate of maternal/fetal

adverse outcomes, a cost-effective sensitivity analysis was performed that assumed that only

detecting and treating OH would result in diminished maternal/fetal complications. Under these

circumstances, universal screening remained highly cost-effective.

Conclusion

In conclusion, the present authors recommend that all women be screened in the first trimester of

pregnancy for thyroid disease. Screening should consist of a TSH level with a reflex FT4

determination if the TSH level is outside the normal limits of pregnancy. All women with OH and

overt hyperthyroidism should be treated immediately. A decision regarding whether to treat SCH

should be made jointly by the clinician and patient following a discussion of the pros and cons of

LT4 intervention.

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Abbreviations

ATA = American Thyroid Association; ATD = antithyroid drug; ES = Endocrine Society; GTT =

gestational transient thyrotoxicosis; hCG = human chorionic gonadotrophin; IQ = intelligence

quotient; IVF = in vitro fertilization; LT4 = levothyroxine; MMI = methimazole; OH = overt

hypothyroidism; PTD = preterm delivery; PTU = propylthiouracil; SCH = subclinical

hypothyroidism; T3 = triiodothyronine; T4 = thyroxine; TAI = thyroid autoimmunity; TBG =

thyroxine-binding globulin; TPOAb = thyroid peroxidase antibody; TRAb = thyroid-stimulating

hormone receptor antibody; TSH = thyroid-stimulating hormone