The Attitude Toward Hypothyroidism During Early Gestation: Time for a Change of Mind?

Abstract

Background:

The approach not to screen thyroid function of all pregnant women is mainly based on conflicting evidence of whether treatment of women with mild hypothyroidism is beneficial. However, there is consensus that all women with overt hypothyroidism (OH) and those with a thyrotropin (TSH) >10 mIU/L should be treated immediately, but data on these conditions are scarce. We assessed the prevalence of OH and a TSH >10 mIU/L during the first trimester of pregnancy.

Methods:

Thyroid function was assessed at 10–12 weeks gestation in 4199 Dutch Caucasian healthy pregnant women from three studies conducted in 2002, 2005, and 2013 from the same iodine sufficient area in the southeast of The Netherlands. We defined the first trimester specific cutoffs (2.5th–97.5th percentile) for TSH and free thyroxine (fT4) in thyroid peroxidase antibody (TPO-Ab) negative women in each study to determine the prevalence of women with OH and those with a TSH >10 mIU/L. We extrapolated these figures to the pregnant population of 2012 in The Netherlands, the United Kingdom, and the United States.

Results:

The prevalence of OH or a TSH >10 mIU/L in these 4199 women was 26 (0.62%) of whom 96% had (highly) elevated TPO-Ab titers. Based on the birth figures of 2012, if all pregnant women from The Netherlands, the United Kingdom or the United States were screened, the conservative annual number of cases would be 1000, 4500, and 25,000 respectively. However, the United Kingdom and parts of the United States have recently been demonstrated to be iodine deficient, which will result in even higher numbers.

Conclusion:

Our findings show that the discussion concerning thyroid screening during pregnancy should be based on data of overt hypothyroidism in healthy pregnant women. Screening of thyroid function is not expensive because all pregnant women have a standardized blood sample test at 8–12 weeks' gestation. Positive patients largely benefit from a cheap, safe, and effective treatment.

Introduction

During the last decade, whether to screen for thyroid function during early pregnancy has been hotly debated. The American Thyroid Association (ATA) pregnancy guidelines published in 2011 recommended against universal screening and advocated a case-finding approach to identify women at high risk for hypothyroidism (1) because “there is insufficient evidence to recommend for or against universal thyrotropin (TSH) screening at the first trimester visit.” In the guidelines published in 2012, The Endocrine Society Task Force (ESTF) could not reach agreement on thyroid testing recommendations for pregnant women (2); some recommended screening while others advocated aggressive case finding in high risk women, an approach similar to the 2011 ATA guidelines. The American Association of Clinical Endocrinologists/ATA (AACCE/ATA) hypothyroidism guidelines also currently recommend a case-finding approach (3). This controversy is mainly based on conflicting evidence that, in case of a mild degree of thyroid dysfunction such as subclinical hypothyroidism (elevated TSH with normal free thyroxine (fT4) levels) or hypothyroxinemia (normal TSH with low fT4 levels), women or their offspring will benefit from treatment with thyroid hormone replacement therapy during pregnancy (4,5). However, there is uniform consensus that “overt hypothyroidism (OH) should be treated in pregnancy. This includes women with a TSH concentration above the trimester-specific reference interval with a decreased free-thyroid hormone (fT4), and all women with a TSH concentration above 10.0 mIU/L, irrespective of the level of fT4’ because “numerous retrospective and case-controlled studies confirm the detrimental effects of OH on pregnancy and fetal health. Though no prospective, randomized investigation of LT4 intervention has occurred in OH pregnant women, such an investigation would be unethical and prohibitive to complete. The available data confirm the benefits of treating OH during pregnancy” (1). Finally, the ATA pregnancy guidelines summarize the basic principles of thyroid function screening in all pregnant women: “The condition must be (a) prevalent in asymptomatic individuals; (b) there must be a reliable and readily available test to identify the cases; (c) there must be a beneficial intervention available; which should be (d) cost-effective” (1).

With regard to OH, there is consensus as far as the last three issues are concerned. However, the question remains of how prevalent untreated OH is in “healthy” pregnant women. There are very few data available in the literature, which was reviewed by Stagnaro-Green in 2011 (6). He concluded that “the actual rate of OH (0.3%) is probably greater because four of the six studies in the review used an upper TSH limit which is now believed to be inappropriately high” (6). Moreover, ethnic differences should also be taken into account (7,8).

To address these issues, we investigated the prevalence of OH and of a TSH >10 mIU/l in white Dutch Caucasian women using strict criteria as advocated by the NHANES (National Health and Nutrition Examination Survey) criteria (1). Subsequently, we extrapolated these findings to figures of the whole pregnant population of Dutch, British, and American Caucasian women in 2012.

Materials and Methods

Subjects

Studies of Dutch Caucasian women were undertaken in the same iodine sufficient area—southeast of The Netherlands—in 2002, 2005, and 2013. All participants were recruited according to the same protocol, and the studies were approved by the Medical Ethical Review Board of the Maxima Medical Hospital Veldhoven. Pregnant women who underwent their first antenatal appointment at the community midwife office (which in general represents 85% of all pregnant women in The Netherlands) were invited for thyroid function screening. The response rate varied between 74% and 82%. Through all three studies, the NHANES exclusion criteria were used: a known history of previous thyroid dysfunction (Hashimoto thyroiditis or Graves' disease, on hormone replacement therapy or not), a known history of autoimmune disease (e.g., diabetes mellitus type 1, rheumatoid arthritis), and the use of drugs that might interfere with thyroid function (e.g., use of lithium in bipolar patients) (1). Women who became pregnant after in vitro fertilization (IVF) or hormone stimulation and women with multiple pregnancies were also excluded. After receiving written informed consent, thyroid function was assessed between 10 and 12 weeks' gestation in all participants; a substantial proportion of these women subsequently participated in a prospective follow-up study throughout gestation. Data analysis in the current study refers only to the thyroid outcome results of the first trimester assessment and included 1354 women from 2002, 1602 women from 2005, and 1243 women from 2013, resulting in a total of 4199 women for the analysis.

Thyroid function assessment in 2003 and 2005

TSH was measured in serum using a solid-phase, two-site chemiluminescent enzyme immunometric assay (IMMULITE Third generation TSH; Diagnostic Products Corporation, Los Angeles, CA). The nonpregnant reference range of TSH is 0.45–4.5 mIU/L. fT4 concentration was measured in serum with a solid-phase immunometric assay (IMMULITE Free T4). The nonpregnant reference range of fT4 is 10.3–25.7 pmol/L. Thyroid peroxide antibodies (TPO-Abs) were determined in serum by means of the IMMULITE Anti-TPO-Ab kit. Women were defined as TPO-Ab-positive when the titer was >35 IU/mL.

Thyroid function assessment in 2013

TSH, fT4, and TPO-Abs were determined in lithium-heparin plasma using electrochemoluminescence assays (Cobas^® e 601; Roche Diagnostics, Mannheim, Germany). The nonpregnant reference range of TSH is 0.40–4.0 mU/L, of fT4 10.0–24.0 pmol/L, and of TPO-Abs <35 kU/L.

Definition of reference range of thyroid function at first trimester

In all three studies, the reference ranges of TSH and fT4 were defined following the same principles. In TPO-Ab negative women, the 2.5th and 97.5th percentiles were used to define the lower and upper limit of normal thyroid function.

Statistical analysis

Statistical analysis was performed using the IBM SPSS Statistics for Windows v19.0 (IBM Corp., Armonk, NY). Descriptive statistics were used to analyze the prevalence of abnormal thyroid dysfunction.

Results

In the 2002 study, 113 (8.3%) of the 1354 women were TPO-Ab-positive. In the 1241 TPO-Ab-negative women, the 2.5th and 97.5th percentiles of TSH and fT4 were 0.11–2.8 mIU/L and 11.2–21.5 pmol/L respectively. In Table 1, the numbers of women of the total group with TSH and fT4 outside this reference range, together with their TPO-Ab status, are shown. There were five women with overt hypothyroidism and two women with a TSH >10 mIU/L; all were TPO-Ab positive.

Table 1.

SH, fT4, and TPO-Ab Status of Women of a General Healthy Pregnant Population with Unknown OH or a TSH >10 mIU/L, Using First Trimester 2.5th and 97.5th Percentile Cutoffs of TSH and fT4 in TPO-Ab Negative Women

	TSH (mIU/L)	fT4 (pmol/L)	TPO-Ab titer IU/mL
2002 study, n=1354
Reference: TSH: 0.11–2.8 mIU/L
fT4: 11.2–21.5 pmol/L
Hypothyroidism:	6.40	10.2	141
	8.72	7.8	1950
	9.70	8.9	450
	14.70	8.7	265
	30.70	6.9	4816
TSH >10 mIU/L:	10.70	12.7	482
	11.84	13.1	792
2005 study, n=1602
Reference: TSH: 0.14–2.9 mIU/L
fT4: 12.0–20.6 pmol/L
Hypothyroidism:	9.2	11.0	31,000
	3.1	11.1	66
	7.9	10.9	3600
	6.2	7.1	2400
	86.0	2.5	930
	4.4	11.0	9
	22.0	9.4	2200
TSH >10 mIU/L:	10.8	13.4	920
	11.4	12.9	389
	14.2	13.2	212
2013 study, n=1243
Reference: TSH: 0.19–3.9 mIU/L
fT4: 11.2–18.0 pmol/L
Hypothyroidism:	120	4.6	550
	5.1	11.0	72
	13.0	11.0	750
	6.7	10.4	230
	8.1	9.9	200
	8.6	10.7	350
TSH >10 mIU/L:	12.0	15.0	350
	11.4	12.9	382
	11.8	11.9	470

TSH, thyrotropin; fT4, free thyroxine; TPO-Ab, thyroid peroxidase antibody; OH, overt hypothyroidism.

This means that 7 of 1354 (0.5%) healthy pregnant women had unknown OH or a TSH >10 mIU/L, all with (markedly) elevated TPO-Ab titers. In the 2005 study, 137 of 1602 women had elevated TPO-Ab (8.5%) titers. The 2.5th and 97.5th percentiles of TSH and fT4 in the 1465 TPO-Ab negative women were 0.14–2.9 mIU/L and 12.0–20.6 pmol/L respectively. As shown in Table 1, there were seven women with OH and three with a TSH >10 mIU/L. This means that of a healthy sample of pregnant women, 10 out of 1602 (0.6%) had unknown OH or a TSH >10 mIU/L. In the 2013 study, 97 of 1243 women (7.8%) had elevated TPO-Ab titers. In the remaining 1146 TPO-Ab-negative women, the 2.5th and 97.5th cutoffs of TSH and fT4 were 0.19–3.9 mIU/L and 11.2–18.0 pmol/L respectively. As shown in Table 1, six women had OH and three had a TSH >10 mIU/L (total of 0.7%). When we take the data of the three studies together, there were 26 of a total of 4199 women with OH or a TSH >10 mIU/L=0.62%. The prevalence of subclinical hypothyroidism (elevated TSH with fT4 within reference limits) in the 2002, 2005, and 2013 studies was 3.4% (n=46), 3.6% (n=58), and 3.3% (n=41) respectively.

We subsequently extrapolated these data to the annual birth-rate figures in The Netherlands where, in 2012 (16 million population, 85% Caucasian), there were 177,000 births (Office for National Statistics 2012). It is well known that about 20% of pregnant women suffer from bleeding during the first 16 weeks, half of which will result in abortion (9). This means that there were approximately 195,000 pregnancies annually, of which 160,000 were of Dutch Caucasian women (estimated, because non-Western people have higher birth-rate figures). Hence, screening all these women would result in the detection of about 992 women with OH or a TSH >10 mIU/L. In the United Kingdom (63 million population), there were 730,000 living births in 2012, from approximately 800,000 pregnancies (Office for National Statistics 2012). Because 84% were from Caucasian mothers, it is estimated that there were 672,000 pregnancies of white Caucasians. Using the data of the current study, this would suggest that screening of all these pregnant women would result in about 4166 women with OH or a TSH >10 mIU/L. In the United States (population 312 million, 80% Caucasian), there were 4,270,000 births in 2012. Based on the National Vital Statistics report of 2012, this birth rate corresponds to more than five million pregnancies. With 80% white Caucasian females and a relatively lower birth rate in this group, a conservative figure of four million white Caucasian pregnancies is estimated. This would mean that by nationwide thyroid screening during gestation, annually about 24,800 pregnant women would be detected with OH or a TSH >10 mIU/L in the United States.

Discussion

The current study underlines the relatively high number of unknown cases of pregnant women with OH (0.6%) in a total sample of 4199 women. The figure has been obtained using first trimester-specific reference ranges for TSH and fT4 assessed in TPO-Ab negative pregnant women under application of the NHANES exclusion criteria. When extrapolating this figure to the annual number of pregnant women in different countries (The Netherlands, the United Kingdom, and the United States), every year a substantial number of women with OH (992, 4166, and 24,800 respectively) are missed, who, according to the ATA pregnancy guidelines, should receive immediate treatment.

The prevalence of elevated TPO-Ab in the three studies (7.8–8.5%) is comparable with the figures in the literature (1) and with two other reports from The Netherlands (7,10). During the last decade, several population-based studies have been published, reporting figures of OH (6). It is beyond the scope of the current study to review these in detail. However, in general, they are difficult to compare because they used different methods of defining cutoffs of reference ranges of TSH and fT4. It is now generally accepted that trimester-specific reference ranges should be defined for both TSH and fT4 in TPO-Ab negative low-risk women (using the NHANES criteria) in each trimester (1). In the absence of these cutoffs, several authors use the TSH cutoff recommended by the ATA of 2.5 mIU/L for the first trimester. Using this cutoff in the current study, this upper limit of 2.5 mIU/L would correspond to the 93th, 92th, and 88th TSH percentile in TPO-Ab negative women in the 2002, 2005, and 2013 samples respectively, resulting in an overall prevalence of OH of 35 (0.8%), of whom 63% were TPO-Ab positive. When in addition the lower cutoff of fT4 of the 5th percentile recommended by the ATA was used (instead of the 2.5th), the overall number of women with OH in the current study would further increase to 46 (1.1%), of whom 54% were TPO-Ab positive. Other studies did assess TSH between 8 and 26 weeks' gestation, but it is well known that with increasing term, the median TSH level increases, making it difficult to use these data to define the first trimester cutoff. Some studies did not include the category of women with a TSH level >10 mIU/L with normal fT4, a subgroup that should also receive immediate treatment as recommended by the ATA pregnancy guidelines (1). Again, other studies with a retrospective design did use a diagnosis of hypothyroidism based on discharge data or extracted from obstetric medical record reports in order to calculate the prevalence number, but it is well known that a substantial number of OH cases are missed when, for example, case finding in high risk women is applied instead of universal screening (11). Most studies reporting high numbers of hypothyroidism (up to 15%) often did not discriminate between subclinical and overt hypothyroidism. Therefore, in Table 2, the prevalence rate of OH is shown of studies using more or less the same (NHANES) criteria as in the current study (5,10 –18). Studies reporting other cutoffs (5th–95th percentiles, not excluding TPO-Ab positive cases) are not included.

Table 2.

Prevalence of Unknown OH and a TSH >10 mIU/L in Healthy First Trimester Pregnant Women in Different Studies, Using Trimester-Specific 2.5th and 97.5th Percentile Cutoffs of TSH and fT4 of TPO-Ab Negative Women

		N (%) of cases
	Total sample size	OH	TSH >10 mIU/L	Total
Casey et al. 2005 (10)	17,298	32 (0.18)	50 (0.29)	82 (0.47)
Vaidya et al. 2007 (11)	1560	16 (1)	3 (0.2)	19 (1.2)
Cleary-Goldman et al. 2008 (12)	10,990	33 (0.3)	?
Wang et al. 2011 (18)	2899	8 (0.3)	?
Lazarus et al. 2012 (5)	21,000	55 (0.26)	69 (0.33)^*	124 (0.59)
Blatt et al. 2012 (16)	117,892	436 (0.36)	?
Medici et al. 2012 (13)	3944	12 (0.3)	?
Potlukova et al. 2012 (14)	5223	21 (0.49)	18 (0.3)	39 (0.75)
Goel et al. 2012 (15)	1005	2 (0.02)	?
Moreno-Reys et al. 2013 (17)	640	5 (0.4)	?

Unpublished data.

The study by Potlukova et al. of 5223 women from the Czech Republic (also an iodine sufficient area) using a similar methodology as the current study showed an overall prevalence rate of 0.75% (0.4% of OH and 0.35% of a TSH >10 mIU/L), which is comparable to the current study (14). The 0.2% of women with isolated TSH levels >10 mIU/L in our study is comparable to the figure of 0.33% of the Controlled Antenatal Thyroid Screening (CATS) study performed in the United Kingdom and Italy (unpublished data) in which more than 20,000 women were screened (5). Another large study from The Netherlands (Generation-R) reported a prevalence of 0.3%, although it does not mention the subgroup with a TSH >10 mIU/L (13). If one assumes a similar number of these women as in the Czech Republic or the current study, their number should increase to 0.5–0.6%, comparable to our study. In the 2011 study by Wang et al. in an iodine sufficient area of China, eight (0.3%) women had OH, with no data on the subgroup with a TSH >10 mIU/L (18). These studies clearly show that there is a variable prevalence of OH (with or without low fT4). The overall number of 0.62% of OH in the current study, resulting in an estimated number of 24,000 women in the United States who annually suffer from undiagnosed OH, is rather close to the estimated figure of Stagnaro-Green of 20,000 (19).

The maternal and fetal adverse outcomes of OH have recently been reviewed elsewhere and are remarkably consistent throughout the literature (6). Maternal adverse outcomes include gestational hypertension, pre-eclampsia, and increased placental weight. Fetal adverse outcomes include cretinism, low birth weight, fetal deaths, spontaneous abortion, intrauterine growth retardation, and pre-eclampsia. These findings are the basis for the well-accepted recommendation that OH during pregnancy should be treated immediately and appropriately (1).

In the current study, up to 96% of the women with OH or a TSH >10 mIU/L had (highly) elevated TPO-Ab titers, which means that thyroid dysfunction was of autoimmune origin. This number dropped to 54% when using a lower TSH upper limit (2.5 mIU/L) and/or a higher fT4 lower limit (5th percentile), suggesting that the 2.5th–97.5th percentile reference range in TPO-Ab negative women of the current study is rather accurate.

The area where the studies were conducted is iodine sufficient as shown in 2001 (20). Moreover, in the 2005 study, results of congenital heel screening in 886 neonates born in 2006 and 2007 resulted in the detection of 13 (1.5%) newborns with a TSH >5 mIU/L, a figure that is <3%, a generally accepted cutoff showing sufficient iodine intake at a population level (21,22). In contrast to The Netherlands, a recent British study revealed iodine deficiency in 737 adolescent schoolgirls: 51% with mild, 16% with moderate, and 1% with severe deficiency (23). A further British study performed in 2013 in 1000 pregnant women found severe and mild-to-moderate iodine deficiency in 7% and 60% of the women respectively (24). During pregnancy, the iodine requirement is sharply elevated, and it has long been demonstrated that iodine deficiency during pregnancy will result in higher maternal TSH levels (22). This implies that more women are expected to have elevated TSH levels, and these should be added to the estimated number of 4166 women with (autoimmune-based) thyroid dysfunction in the United Kingdom. The United States is considered a relatively iodine sufficient country, although there are concerns that this may not be the case for all pregnant women, especially during the first trimester (25). During recent decades, the discussion on whether to screen for thyroid function has focused on the relevance of detecting subtle (subclinical) thyroid dysfunction during early gestation, prevalent in 1–3% of the general pregnant population (1). Because the negative consequences on pregnancy outcomes for both mother and child are still debated, and the few intervention studies showed rather conflicting results (4,5), there is still no agreement for advocating universal screening. However, we and others, as recently stated in a review on thyroid dysfunction during gestation, feel that it is time for a change of mind (26,27). If one focuses on OH and a TSH >10 mIU/L (both conditions that should definitely be treated) instead of subclinical hypothyroidism, the number of women that would annually be found in our country (at least 1000, all ethnic groups included), in the United Kingdom (at least 4500, all ethnic groups included), and in the United States (up to 25,000 women, all ethnic groups included) make screening of all pregnant women worthwhile. It does not make sense to state that because we do not know whether there is any benefit of treating a relatively large group of pregnant women with mild (sub-clinical) hypothyroidism that will be found when screening is implemented, we do not advocate nationwide screening, although we know that there is a (smaller) group of women that will be found during screening with untreated serious overt hypothyroidism to whom it is even unethical not offering treatment. The TSH test is reliable, cheap, and easy to perform: all pregnant women in Western societies have a standardized blood assessment at 8–12 weeks' gestation. Adding a TSH measurement would cost 6–12 US dollars. Subsequent treatment with T4 is also cheap, effective, and safe. The studies that investigated the cost-effectiveness of screening showed that universal screening was by far the most cost-effective strategy (28,29).

We feel that the high number of “healthy” pregnant women with unknown severe hypothyroidism according to recent reference criteria of trimester-specific normal thyroid function in an iodine sufficient area underlines the need of screening the thyroid function of the general pregnant population.

Footnotes

Acknowledgment

We would like to thank all the community midwives of the southeast area of The Netherlands for their participation into the recruitment of pregnant women for more than a decade.

Author Disclosure Statement

The authors declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work.

References

Stagnaro-Green

, Abalovich

, Alexander

, Azizi

, Mestman

, Negro

, Nixon

, Pearce

, Soldin

, Sullivan

, Wiersinga

. 2011. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid, 10:1081–1125.

De Groot

, Abalovich

, Alexander

, Amino

, Barbour

, Cobin

, Eastman

, Lazarus

, Luton

, Mandel

, Mestman

, Rovet

, Sullivan

. 2012. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 97:2543–2565.

Garber

, Cobin

, Gharib

, Hennessey

, Klein

, Mechanick

, Pessah-Pollack

, Singer

, Woeber

. 2012. Clinical practice guidelines for hypothyroidism in adults: co-sponsored by American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract, 18:988–1028.

Negro

, Formoso

, Mangieri

, Pezzarossa

, Dazzi

, Hassan

. 2006. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab, 91:2587–2591.

Lazarus

, Bestwick

, Channon

, Paradice

, Maina

, Rees

, Chiusano

, John

, Guaraldo

, George

, Perona

, Dall'Amico

, Parkes

, Joomun

, Wald

. 2012. Antenatal thyroid screening and childhood cognitive function. N Engl J Med, 366:493–501.

Stagnaro-Green

. 2011. Overt hyperthyroidism and hypothyroidism during pregnancy. Clin Obstet Gynecol, 54:478–487.

Benhadi

, Wiersinga

, Reitsma

, Vrijkotte

, van der Wal

, Bonsel

. 2007. Ethnic differences in TSH but not in free T4 concentrations or TPO antibodies during pregnancy. Clin Endocrinol, 66:765–770.

Korevaar

, Medici

, de Rijke

, Visser

, de Muinck Keizer-Schrama

, Jaddoe

, Hofman

, Ross

, Visser

, Hooijkaas

, Steegers

, Tiemeier

, Bongers-Schokking

, Visser

, Peeters

. 2013. Ethnic differences in maternal thyroid parameters during pregnancy: the Generation R study. J Clin Endocrinol Metab, 98:3678–3686.

Everett

. 1997. Incidence and outcome of bleeding before the 20th week of pregnancy: prospective study from general practice. Br Med J, 315:32–34.

10.

Casey

, Dashe

, Wells

, McIntire

, Byrd

, Leveno

, Cunningham

. 2005. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol, 105:237–245.

11.

Vaidya

, Anthony

, Bilous

, Shields

, Drury

, Hutchison

, Bilous

. 2007. Detection of thyroid dysfunction in early pregnancy: universal screening or targeted high risk case-finding?. J Clin Endocrinol Metab, 92:203–207.

12.

Cleary-Goldman

, Malone

, Lambert-Messerlian

, Sullivan

, Canick

, Porter

, Luthy

. 2008. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol, 112:85–92.

13.

Medici

, de Rijke

, Peeters

, Visser

, de Muinck Keizer-Schrama

, Jaddoe

, Hofman

, Hooijkaas

, Steegers

, Tiemeier

, Bongers-Schokking

, Visser

. 2012. Maternal early pregnancy and newborn thyroid hormone parameters: the Generation-R study. J Clin Endocrinol Metab, 97:646–652.

14.

Potlukova

, Potluka

, Jiskra

, Limanova

, Telicka

, Bartakova

, Springer

. 2012. Is age a risk factor for hypothyroidism in pregnancy? An analysis of 5223 pregnant women. J Clin Endocrinol Metab, 97:1945–1952.

15.

Goel

, Kaur

, Saha

, Tendon

, Devi

. 2012. Prevalence, associated risk factors and effects of hypothyroidism in pregnancy: a study from North India. Gynecol Obstet Invest, 74:89–94.

16.

Blatt

, Nakamoto

, Kaufman

. 2012. National status of testing for hypothyroidism during pregnancy and postpartum. J Clin Endocrinol Metab, 97:777–784.

17.

Moreno-Reyes

, Glinoer

, Ovyen van

, Vandevijvere

. 2013. High prevalence of thyroid disorders in pregnant women in a mildly iodine deficient country; a population based study. J Clin Endocrinol Metab, 98:3694–3701.

18.

Wang

, Teng

, Shan

, Wang

, Li

, Zhu

, Zhou

, Mao

, Yu

, Li

, Chen

, Xue

, Fan

, Wang

, Zhang

, Li

, Zhou

, Gao

, Shang

, Zhou

, Ding

, Ma

, Wu

, Xu

, Liu

. 2011. The prevalence of thyroid disorders during early pregnancy in China: the benefits of universal screening in the first trimester. Eur J Endocrinol, 164:263–268.

19.

Stagnaro-Green

. 2012. Optimal care of the pregnant woman with thyroid disease. J Clin Endocrinol Metab, 97:2619–2620.

20.

Wiersinga

, Podoba

, Srbecky

, van Vessem

, van Beeren

, Platvoet-Ter Schiphorst

. 2001. A survey of iodine intake and thyroid volume in Dutch schoolchildren: reference values in an iodine-sufficient area and the effect of puberty. Eur J Endocrinol, 144:595–603.

21.

Kuppens

, Kooistra

, Wijnen

, Vader

, Hasaart

, Oei

, Vulsma

, Pop

. 2011. Neonatal thyroid screening results are related to gestational maternal thyroid function. Clin Endocrinol (Oxf), 75:382–387.

22.

Zimmerman

. 2009. Iodine deficiency in pregnancy and the effect of maternal iodine supplementation on the offspring: a review. Am J Clin Nutr, 89:668S–672S.

23.

Vanderpump

, Lazarus

, Smyth

, Laurberg

, Holder

, Boelaert

, Franklyn

. 2011. British Thyroid Association UK Iodine Survey Group. Iodine status of UK schoolgirls: a cross-sectional survey. Lancet, 377:2007–2012.

24.

Bath

, Steer

, Golding

, Emmett

, Rayman

. 2013. Effect of inadequate iodine status in UK pregnant women on cognitive outcomes in their children: results from the Avon Longitudinal Study of Parents and Children (ALSPAC). Lancet, 382:331–337.

25.

Caldwell

, Pan

, Mortensen

, Makhmudov

, Merrill

, Moye

. 2013. Iodine status in pregnant women in the National Children's Study and in U.S. women (15–44 years), National Health and Nutrition Examination Survey 2005–2010. Thyroid, 23:927–937.

26.

Pop

, van Baar

, Vulsma

. 1999. Should all pregnant women be screened for hypothyroidism?. Lancet, 354:1224–1225.

27.

Laurberg

, Andersen

, Pedersen

, Andersen

, Carlé

. 2013. Screening for overt thyroid disease in early pregnancy may be preferable to searching for small aberrations in thyroid function tests. Clin Endocrinol (Oxf), 79:297–304.

28.

Thung

, Funai

, Grobman

. 2009. The cost-effectiveness of universal screening in pregnancy for subclinical hypothyroidism. Am J Obstet Gynecol. 200:267.e1–7.

29.

Dosiou

, Barnes

, Schwartz

, Negro

, Crapo

, Stagnaro-Green

. 2012. Cost-effectiveness of universal and risk-based screening for autoimmune thyroid disease in pregnant women. J Clin Endocrinol Metab, 97:1536–1546.