Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2016 Feb 26.
Published in final edited form as: Am J Med Genet A. 2015 Feb 5;0(4):701–707. doi: 10.1002/ajmg.a.36953

Craniosynostosis and Risk Factors Related to Thyroid Dysfunction

S L Carmichael 1, C Ma 1,*, S A Rasmussen 2, M L Cunningham 3, M L Browne 4,5, C Dosiou 6, E J Lammer 7, G M Shaw 1
PMCID: PMC4768483  NIHMSID: NIHMS761937  PMID: 25655789

Abstract

Thyroid disease is a common problem among women of reproductive age but often goes undiagnosed. Maternal thyroid disease has been associated with increased risk of craniosynostosis. We hypothesized that known risk factors for thyroid disease would be associated with risk of craniosynostosis among women not diagnosed with thyroid disease. Analyses included mothers of 1,067 cases and 8,494 population-based controls who were interviewed for the National Birth Defects Prevention Study. We used multivariable logistic regression to estimate adjusted odds ratios (AOR) and 95% confidence intervals (CI). After excluding women with diagnosed thyroid disease, younger maternal age (AOR 0.7, 95% CI 0.6–0.9, for <25 years versus 25–29), black or other race-ethnicity (AOR 0.3, 95% CI 0.2–0.4 and AOR 0.6, 95% CI 0.4–0.8, respectively, relative to non-Hispanic whites), fertility medications or procedures (AOR 1.5, 95% CI 1.2–2.0), and alcohol consumption (AOR 0.8, 95% CI 0.7–0.9) were associated with risk of craniosynostosis, based on confidence intervals that excluded 1.0. These associations with craniosynostosis are consistent with the direction of their association with thyroid dysfunction (i.e., younger age, black race-ethnicity and alcohol consumption are associated with reduced risk and fertility problems are associated with increased risk of thyroid disease). This study thus provides support for the hypothesis that risk factors associated with thyroid dysfunction are also associated with risk of craniosynostosis. Improved understanding of the potential association between maternal thyroid function and craniosynostosis among offspring is important given that craniosynostosis carries significant morbidity and that thyroid disease is under-diagnosed and potentially modifiable.

Keywords: craniosynostosis, thyroid, birth defects

INTRODUCTION

Thyroid disease is a common condition among women of reproductive age. Hypothyroidism affects 2–5% of pregnant women, whereas current or past hyperthyroidism (primarily Graves’ disease) affects about 1% [Laurberg et al., 1998; Casey et al., 2006]. Presence of anti-thyroid antibodies is much more common, observed in 13% of pregnant women without recognized thyroid disease in a large US study [Haddow et al., 2010]. Even in the absence of overt thyroid disease, these antibodies are associated with higher levels of thyroid stimulating hormone (TSH) and are predictive of the development of overt thyroid disease. In addition, transient hyperthyroidism (thyrotoxicosis) affects up to 3% of women during early pregnancy, due to the TSH-like activity of placental hCG (human chorionic gonadotropin) [Glinoer, 1998]. Hypo- and hyperthyroidism, as well as the presence of anti-thyroid antibodies in the absence of thyroid disease, are associated with increased risk of adverse pregnancy outcomes such as spontaneous abortion and preterm delivery [van den Boogaard et al., 2011; He et al., 2012; Mannisto et al., 2013]. Improved understanding of the association of maternal thyroid function with reproductive outcomes is particularly important given that thyroid disease often goes undiagnosed [Hollowell et al., 2002], and the appropriate approach to screening and management of thyroid disease during pregnancy is a topic of ongoing debate [Stagnaro-Green and Pearce, 2012].

Craniosynostosis (CS), the premature fusion of one or more cranial sutures, leads to abnormal craniofacial form and function. It may be associated with increased intracranial pressure leading to abnormal neurocognitive development, and most affected infants require extensive reconstructive surgery [Speltz et al., 2004; Rasmussen et al., 2008; Starr et al., 2012]. Wehypothesize that maternal thyroid hormones or anti-thyroid antibodies may result in exposure of fetal tissues to excessive amounts of thyroid hormone, which in turn may cause premature suture fusion. A variety of case-only studies suggest that thyroid hormones may be associated with craniosynostosis [Penfold and Simpson, 1975; Johnsonbaugh et al., 1978; Daneman and Howard, 1980; Cove and Johnston, 1985; Leonard et al., 1987; Stevenson and Trent, 1990; Nishihara et al., 2006].More recently, Rasmussen et al. reported an association of thyroid disease with risk of craniosynostosis using data from the National Birth Defects Prevention Study [Rasmussen et al., 2007]. One explanation for these findings is that thyroid hormones stimulate osteogenesis. In particular, treatment with thyroid hormones has been shown to stimulate osteogenesis of the skull and premature narrowing of cranial sutures in experimental studies [Akita et al., 1994].

Many risk factors for thyroid disease have been identified, such as older maternal age, white or Hispanic race-ethnicity, and higher body mass index [Hollowell et al., 2002; Knudsen et al., 2005]. In this study, we examined whether risk factors for thyroid disease, among mothers who did not report having thyroid disease, were associated with increased risk of craniosynostosis.

METHODS

Study Design and Data Collection

This study included data on deliveries that occurred from 1997 to 2007 and were part of the NBDPS, a case-control study of birth defects that was conducted in ten states of the U.S. Details about study design and methods have been published [Cogswell et al., 2009; Yoon et al., 2001]. Most study sites included liveborn infants, fetal deaths (at greater than 20 weeks gestation), and electively terminated cases. Each site selected a population-based set of nonmalformed, liveborn control infants during each study year from birth certificates or birth hospitals.

Information on case infants was obtained from hospital reports and medical records [Rasmussen et al., 2003], and one clinical geneticist (SAR) provided a final review of all cases to ensure that they all met standard eligibility criteria. All craniosynostosis cases were verified by radiographic imaging (e.g., skull radiograph or head CT) or surgery. Infants with recognized or strongly suspected single-gene disorders or chromosomal abnormalities were ineligible. The specific suture(s) involved was also identified (i.e., sagittal, coronal, metopic, lambdoid, multiple, or unknown). Infants with more than one type of involved suture (e.g., sagittal and coronal sutures both prematurely closed) were counted only in the multiple suture category.

Maternal interviews were conducted using a standardized, computer-based questionnaire by telephone, in English or Spanish. Interviews were conducted with 71% of eligible case mothers and 66% of eligible control mothers. The median time from delivery to interview was 14 months for cases and 8 months for controls.

Study Variables

Maternal thyroid disease was based on a mother’s report of a thyroid disorder or taking thyroid medication at any time during pregnancy [Rasmussen et al., 2007]. This information was in response to general questions about medical conditions; questions specifically about thyroid disease were not asked. We examined the association of craniosynostosis with the following factors related to maternal thyroid dysfunction: maternal age, race-ethnicity, parity, pre-pregnancy body mass index (BMI), fertility medications or procedures (as a proxy for fertility problems), previous miscarriages, diabetes, hypertension, intake of anti-depressants (a proxy for depression) or iron-only supplements (a proxy for anemia), smoking, and alcohol consumption [Glinoer 1998; Hollowell et al., 2002; Belin et al., 2004; Knudsen et al., 2005; Zimmermann et al., 2007; Ashoor et al., 2010; Carle et al., 2012a; Carle et al., 2012b; De Groot et al., 2012; Wu et al., 2013].

Analysis

First, we examined the association of maternal thyroid disease with craniosynostosis, given that our previous analysis of this study question only included data on births through 2002 [Rasmussen et al., 2007]. The current analysis was adjusted only for maternal age, as was done for the previous study. We used logistic regression to estimate odds ratios (OR) and 95 percent confidence intervals (CI). Second, we examined the association of each covariate with maternal report of thyroid disease among the controls, using Chi-square tests. Third, we conducted logistic regression models that included all covariates but that excluded women who reported thyroid disease, to determine the independent association of each covariate with craniosynostosis. We examined associations with craniosynostosis overall and with each suture type separately.

RESULTS

There were 1,067 cases and 8,494 controls available for analysis. The sagittal suture was affected in 566 (53%) cases, the metopic suture in 194 (18%), the coronal suture in 187 (18%), the lambdoid suture in 32 (3%), multiple sutures in 85 (8%), and unspecified in three (0.3%). A total of 37 case mothers (3.5%) and 191 control mothers (2.3%) reported thyroid disease. Most women with thyroid disease did not specify the type of thyroid disease (81% of affected case mothers, 87% of affected control mothers), and many women with thyroid disease did not report intake of a specific thyroid-related medication (19% of cases, 35% of controls). Among those that did report taking a medication, most reported taking levothyroxine (93% of cases, 94% of controls). The adjusted OR for craniosynostosis and maternal thyroid disease was 1.4 (95% CI 0.9, 1.9). ORs were similar for specific affected sutures, with the exception of multiple affected sutures, for which the OR was 3.0 (95% CI 1.3, 6.9) (Table I).

TABLE I.

Association of Maternal Thyroid Disease With Craniosynostosis, National Birth Defects Prevention Study, 1997–2007

Affected suture(s) No. cases with and without thyroid disease* AOR (95% CI), adjusted for maternal age**
Any 37/1030 1.4 (0.9, 1.9)
Sagittal 19/547 1.3 (0.8, 2.1)
Metopic 6/188 1.3 (0.6, 3.0)
Coronal 6/181 1.2 (0.5, 2.9)
Lambdoidal 0/32 —
Multiple 6/79 3.0 (1.3, 6.9)
Open in a new tab
*

The sum of the two numbers in the column equals the total number of cases; eg, 37 + 1030 = 1067 cases with any affected suture. Number of controls with and without thyroid disease was 191 and 8303, respectively.

**

Adjusted for maternal age as <25, 25–29, 30–34, 35+ years.

Relative to control mothers who did not report thyroid disease, control mothers who did report thyroid disease were more likely to be older, be non-Hispanic white, report fertility medications or procedures, have had a previous miscarriage, have gestational diabetes, and take anti-depressants or iron-only supplements, and less likely to smoke, based on P<0.05 (Table II). Parity, BMI, hypertension and alcohol consumption were not statistically different (P≥0.05).

TABLE II.

Association of Maternal Characteristics With Thyroid Disease Among Control Mothers

Percent, among mothers with
thyroid disease (n = 191)* 		Percent, among mothers without
thyroid disease (n = 8,303)* 		P-value
Age (years) <0.001
   <25 11 34
   25–29 29 27
   30–34 34 25
   35 or older 27 14
Race-ethnicity <0.001
   Non-Hispanic white 73 58
   Non-Hispanic black 4 11
   Hispanic 14 23
   Other 8 8
Parity (previous live births)
   0 33 40 0.132
   1 37 33
   2 or more 30 27
Pre-pregnancy body mass index**
   Underweight (<18.5 kg/m2) 3 5 0.066
   Normal weight (18.5–24.9 kg/m2) 49 53
   Overweight (25.0–29.9 kg/m2) 25 22
   Obesity (30–39.9 kg/m2) 20 14
   Extreme obesity (40 or more kg/m2) 3 2
Fertility medications or procedures 12 4 <0.001
Previous miscarriage
   None 68 78 0.005
   1 25 16
   2 or more 7 6
Diabetes
   None 87 93 0.037
   Pre-gestational 1 1
   Gestational 11 6
Hypertension before or during pregnancy 12 13 0.689
Took anti-depressants (from 3 months
  before or during pregnancy)		 7 4 0.047
Took iron-only supplement
   None 77 72 0.029
   Began in 1st trimester 7 13
   Began in 2nd trimester 9 11
   Began in 3rd trimester 6 4
Smoked (1st trimester) 9 16 0.016
Alcohol consumption (1st trimester) 25 22 0.245
Open in a new tab
*

Column percents do not add to 100% due to missing data.

We then examined the association of the studied risk factors with craniosynostosis after adjustment for all other factors and excluding women who reported thyroid disease. Maternal younger age (OR 0.7,95% CI 0.6–0.8, for <25 years vs. 25–29), black (OR 0.3, 95% CI 0.2–0.4) or other race-ethnicity (OR 0.6, 95% CI 0.4–0.8), fertility medications or procedures (OR 1.5, 95% CI 1.2–2.0), and alcohol consumption (OR 0.8, 95% CI 0.7–0.9) were associated with risk of craniosynostosis, based on confidence intervals that excluded 1.0 (Table III). Many results were similar regardless of suture type but a few differences from all cases grouped together are noteworthy: sagittal synostosis had the weakest association with fertility treatments; risk of coronal synostosis was not reduced among infants born to mothers with Hispanic and other race-ethnicity; and risk of coronal synostosis was elevated among infants born to mothers with pre-gestational diabetes. Several results were different for lambdoid cases but should be interpreted with caution given that analyses of this group included only 31 cases (Table III).

TABLE III.

Association of Maternal Characteristics With Risk of Craniosynostosis, Overall and by Affected Suture(s), Among Mothers Who Did Not Have Thyroid Disease

Adjusted Odds Ratio (95% CI)*
All cases
(n = 962)		 Sagittal
(n = 513)		 Metopic
(n = 174)		 Coronal
(n = 169)		 Lambdoidal
(n = 31)		 Multiple suture
(n = 72)
Age (years)
   <25 0.7 (0.6, 0.9) 0.6 (0.5, 0.8) 0.9 (0.6, 1.3) 0.7 (0.5, 1.2) 0.4 (0.1, 1.2) 1.0 (0.5, 1.9)
   25–29 Ref Ref Ref Ref Ref Ref
   30–34 1.1 (0.9, 1.4) 1.0 (0.8, 1.2) 1.2 (0.8, 1.7) 1.9 (1.3, 2.8) 1.3 (0.5, 3.5) 0.8 (0.4, 1.5)
   35 or older 1.2 (1.0, 1.5) 1.2 (0.9, 1.5) 1.0 (0.6, 1.7) 1.2 (0.7, 2.1) 2.5 (0.9, 6.9) 1.6 (0.8, 3.1)
Race-ethnicity
   Non-Hispanic white Ref Ref Ref Ref Ref Ref
   Non-Hispanic black 0.3 (0.2, 0.4) 0.2 (0.1, 0.4) 0.6 (0.3, 1.1) 0.3 (0.1, 0.7) – 0.1 (0.01, 0.7)
   Hispanic 0.8 (0.7, 1.0) 0.6 (0.4, 0.7) 0.8 (0.5, 1.2) 1.5 (1.0, 2.2) 3.4 (1.5, 7.9) 0.7 (0.4, 1.4)
   Other 0.6 (0.4, 0.8) 0.4 (0.3, 0.7) 0.5 (0.2, 1.0) 1.3 (0.7, 2.2) 0.6 (0.1, 5.0) 0.2 (0.02, 1.1)
Parity (previous live births)
   0 Ref Ref Ref Ref Ref Ref
   1 1.1 (1.0, 1.3) 1.2 (1.0, 1.5) 0.9 (0.6, 1.2) 1.1 (0.8, 1.6) 0.7 (0.3, 1.6) 1.3 (0.7, 2.3)
   2 or more 1.0 (0.8, 1.2) 1.2 (0.9, 1.5) 0.7 (0.4, 1.0) 1.0 (0.6, 1.5) 0.2 (0.1, 0.7) 1.2 (0.6, 2.3)
Pre-pregnancy body mass index
   Underweight (<18.5 kg/m2) 1.1 (0.8, 1.5) 1.2 (0.8, 1.9) 0.8 (0.4, 1.9) 0.9 (0.4, 2.0) 0.7 (0.1, 5.0) 1.9 (0.8, 4.6)
   Normal weight (18.5–24.9 kg/m2) Ref Ref Ref Ref Ref Ref
   Overweight (25.0–29.9 kg/m2) 1.1 (1.0, 1.3) 1.1 (0.9, 1.4) 1.5 (1.0, 2.2) 0.9 (0.6, 1.4) 1.0 (0.4, 2.5) 1.2 (0.7, 2.1)
   Obesity (30–39.9 kg/m2) 1.2 (1.0, 1.5) 1.2 (0.9, 1.5) 1.5 (1.0, 2.3) 1.3 (0.8, 1.9) 1.3 (0.5, 3.5) 1.0 (0.5, 2.1)
   Extreme obesity (40 or more kg/m2) 1.2 (0.7, 1.8) 1.0 (0.5, 1.9) 1.9 (0.8, 4.5) 1.8 (0.8, 4.0) – –
Fertility medications or procedures 1.5 (1.2, 2.0) 1.2 (0.8, 1.7) 2.3 (1.4, 3.7) 1.7 (1.0, 3.0) 1.6 (0.5, 5.6) 1.3 (0.5, 3.3)
Previous miscarriage
   None Ref Ref Ref Ref Ref Ref
   1 1.1 (0.9, 1.3) 1.0 (0.8, 1.3) 1.4 (1.0, 2.0) 1.0 (0.7, 1.5) 2.3 (1.1, 5.0) 0.7 (0.4, 1.5)
   2 or more 1.1 (0.8, 1.5) 1.2 (0.9, 1.7) 1.3 (0.7, 2.4) 0.8 (0.4, 1.5) 0.6 (0.1, 4.7) 0.8 (0.3, 2.2)
Diabetes
   None Ref Ref Ref Ref Ref Ref
   Pre-gestational 1.2 (0.5, 2.5) 0.8 (0.3, 2.7) 0.8 (0.1, 6.1) 3.4 (1.2, 10.0) – –
   Gestational 1.3 (1.0, 1.6) 1.3 (1.0, 1.9) 0.8 (0.4, 1.6) 1.4 (0.9, 2.4) 1.7 (0.5, 5.8) 1.7 (0.8, 3.9)
Hypertension (before or during pregnancy) 1.1 (0.9, 1.3) 1.1 (0.9, 1.5) 0.8 (0.5, 1.3) 1.2 (0.8, 1.8) 0.7 (0.2, 2.3) 1.1 (0.5, 2.1)
Took anti-depressants (from 3 months before or
  during pregnancy)		 1.3 (1.0, 1.8) 1.4 (1.0, 2.0) 1.2 (0.6, 2.4) 1.2 (0.6, 2.4) 2.4 (0.7, 8.3) 1.2 (0.4, 3.3)
Took iron supplements
   None Ref Ref Ref Ref Ref Ref
   Began in 1st trimester 1.1 (0.9, 1.3) 1.0 (0.7, 1.3) 1.2 (0.8, 1.8) 1.1 (0.7, 1.7) 1.5 (0.6, 3.7) 1.0 (0.5, 2.1)
   Began in 2nd trimester 0.8 (0.6, 1.1) 1.0 (0.7, 1.3) 0.7 (0.4, 1.2) 0.8 (0.4, 1.4) – 0.8 (0.3, 1.8)
   Began in 3rd trimester 0.8 (0.5, 1.2) 1.0 (0.6, 1.5) 0.7 (0.3, 1.8) 0.8 (0.3, 1.9) 0.7 (0.1, 5.5) –
Smoking (1st trimester) 1.0 (0.8, 1.2) 1.0 (0.7, 1.3) 0.8 (0.5, 1.3) 1.2 (0.8, 1.8) 3.2 (1.4, 7.3) 0.6 (0.3, 1.3)
Alcohol consumption (1st trimester) 0.8 (0.7, 0.9) 0.8 (0.6, 1.0) 0.8 (0.6, 1.2) 0.8 (0.5, 1.1) 1.5 (0.7, 3.2) 0.8 (0.4, 1.4)
Open in a new tab
*

All odds ratios are adjusted for all other variables in the table. All models included 7,417 controls. Cases (n = 68 of 1,030) and controls (n = 886 of 8,303) with missing data on any covariates were excluded. Bold font indicates 95 % CI excluding 1.0 before rounding into one decimal place.

DISCUSSION

We examined the association of craniosynostosis with several maternal characteristics that are related to increased risk of thyroid disease, among women who did not report having thyroid disease. After adjustment for all other studied factors, reduced risk of craniosynostosis was observed among babies born to women who were younger, had black or other race-ethnicity, and consumed alcohol, and increased risk was observed among women who took fertility medications or had fertility-related procedures. The directions of the associations of these risk factors with craniosynostosis are consistent with the directions of their associations with thyroid dysfunction. The findings thus lend support to a potential association of craniosynostosis with thyroid dysfunction, even among women who have not been diagnosed with overt thyroid disease.

The associations of craniosynostosis with many of the studied risk factors have been studied previously [Reefhuis et al., 2003; Carmichael et al., 2008; Boulet et al., 2010; Sanchez-Lara et al., 2010; Richardson et al., 2011]. The novelty of the current study is that they have been examined simultaneously in the context of a unifying hypothesis regarding thyroid disease, and they have all been adjusted for confounding by each other. Previous studies have typically focused on one or a few risk factors at a time, adjusted for fewer covariates, included fewer cases, and did not exclude women diagnosed with overt thyroid disease.

Ideally, we would like to examine directly whether maternal thyroid hormone levels or the presence of anti-thyroid antibodies are associated with craniosynostosis. Given that such measurements were not available and would be very difficult to obtain prospectively given the rarity of craniosynostosis, we took the alternative approach of studying risk factors for thyroid dysfunction. This is akin to an approach that has been used to understand the association of estrogen-related exposures with hypospadias and testicular cancer [Carmichael et al., 2007; English et al., 2003]. Initial analyses confirmed that most of the studied maternal characteristics were indeed associated with reported thyroid disease among control mothers. This lends internal validity to our approach.

In our previous analysis of the association of maternal self-reported thyroid disease with craniosynostosis, which was based on births from 1997–2002, the OR was 2.3 (95% CI 1.4, 4.0). In that study, 4.4% of case mothers (19/431) and 1.6% of control mothers (65/4,094) reported having thyroid disease. In the current study, which includes births from 1997–2007, the respective OR and percentages are 1.4 (95% CI 0.9, 1.9), 3.5% and 2.3% of controls. We do not have an explanation for the difference in results using more recent data. Many case reports and series that involve varied scenarios of maternal or newborn thyroid dysfunction have suggested an association with craniosynostosis [Penfold and Simpson, 1975; Johnsonbaugh et al., 1978; Daneman and Howard, 1980; Cove and Johnston, 1985; Leonard et al., 1987; Stevenson and Trent, 1990; Nishihara et al., 2006]. The osteogenic effects of thyroid hormone and experimental data also support the hypothesis [Akita et al., 1994]. Supportive observational epidemiologic data are limited, with the NBDPS offering the largest set of detailed observational data to date that can be used to address this question. Several other epidemiologic studies have examined the association of maternal thyroid disease with birth defects, but sample sizes have been quite limited [Momotani et al., 1984; Khoury et al., 1989; Wing et al., 1994; Chen et al., 2011; Yoshihara et al., 2012; Andersen et al., 2013; Kallen and Norstedt Wikner, 2014]. A large study of Texas births reported lower thyroxine levels in newborn screening bloodspots among infants with craniosynostosis [Hashmi et al., 2012], a finding that could be expected if the mothers were hyperthyroid during pregnancy.

We acknowledge that thyroid dysfunction and its association with the studied risk factors are complex. For example, alcohol consumption has recently been shown to be protective against development of autoimmune hypo- or hyperthyroidism [Carle et al., 2012b], which supports our observation of reduced risk among women who drank. Another example is smoking. Some studies have suggested that smoking is associated with increased risk of craniosynostosis [Kallen, 1999; Honein and Rasmussen, 2000; Carmichael et al., 2008]. However, a recent report suggested that smoking cessation was associated with increased incidence of hypothyroidism [Carle et al., 2012a]. We would certainly not advocate alcohol consumption or smoking during pregnancy, but this information is potentially useful from an etiologic standpoint and from the perspective of trying to synthesize varied findings. We would also like to note that although the findings do lend support to our hypothesis, mechanisms other than undiagnosed thyroid dysfunction could also explain the observed associations.

Strengths of the current study include its population-based, multi-center design, careful case ascertainment, large size, suture-specific analyses, and simultaneous examination of multiple risk factors. Interviews were conducted with mothers of 71% of eligible cases and 66% of controls. We have no reason to believe that participation was differentially related to the studied risk factors for cases versus controls, but if it was, then selection bias may have affected our results. Similarly, we do not know whether mothers’ recall of any risk factors was related to case or control status, but if it was, then recall bias could have affected our results.

This study’s findings provide support for the hypothesis that risk factors associated with thyroid dysfunction are also associated with risk of craniosynostosis. Improving our understanding of the potential association between maternal thyroid function and craniosynostosis among offspring is important, given that thyroid disease is common, under-diagnosed and potentially modifiable.

Acknowledgments

Grant sponsor: Centers for Disease Control; Grant sponsor: Prevention Centers of Excellence; Grant number: Award No. U50/CCU925286 and U01DD001033; Grant sponsor: NIH; Grant number: R03 DE019521.

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, the National Institute of Child Health and Human Development, the National Institutes of Health, or the California Department of Public Health. We thank the California Department of Public Health, Maternal Child and Adolescent Health Division for providing surveillance data from California for this study. Drs. Carmichael, Cunningham, Lammer and Shaw have received compensation as expert witnesses for litigation related to anti-depressant medications and birth defects.

REFERENCES

  1. Akita S, Nakamura T, Hirano A, Fujii T, Yamashita S. Thyroid hormone action on rat calvarial sutures. Thyroid. 1994;4:99–106. doi: 10.1089/thy.1994.4.99. [DOI] [PubMed] [Google Scholar]
  2. Andersen SL, Olsen J, Wu CS, Laurberg P. Birth defects after early pregnancy use of antithyroid drugs: a Danish nationwide study. J Clin Endocrinol Metab. 2013;98:4373–4381. doi: 10.1210/jc.2013-2831. [DOI] [PubMed] [Google Scholar]
  3. Ashoor G, Maiz N, Rotas M, Kametas NA, Nicolaides KH. Maternal thyroid function at 11 to 13 weeks of gestation and subsequent development of preeclampsia. Prenat Diagn. 2010;30:1032–1038. doi: 10.1002/pd.2566. [DOI] [PubMed] [Google Scholar]
  4. Belin RM, Astor BC, Powe NR, Ladenson PW. Smoke exposure is associated with a lower prevalence of serum thyroid autoantibodies and thyrotropin concentration elevation and a higher prevalence of mild thyrotropin concentration suppression in the third National Health and Nutrition Examination Survey (NHANES III) J Clin Endocrinol Metab. 2004;89:6077–6086. doi: 10.1210/jc.2004-0431. [DOI] [PubMed] [Google Scholar]
  5. Boulet SL, Rasmussen SA, Honein MA. Maternal body mass index as a risk factor for craniosynostosis. Am J Med Genet A. 2010;152A:2895–2897. doi: 10.1002/ajmg.a.33668. [DOI] [PubMed] [Google Scholar]
  6. Carle A, Pedersen Bulow, Knudsen I, Perrild N, Ovesen H, Banke L, Rasmussen L, Jorgensen T, Laurberg P. Smoking cessation is followed by a sharp but transient rise in the incidence of overt autoimmune hypothyroidism - a population-based, case-control study. Clin Endocrinol (Oxf) 2012a;77:764–772. doi: 10.1111/j.1365-2265.2012.04455.x. [DOI] [PubMed] [Google Scholar]
  7. Carle A, Pedersen IB, Knudsen N, Perrild H, Ovesen L, Rasmussen LB, Jorgensen T, Laurberg P. Moderate alcohol consumption may protect against overt autoimmune hypothyroidism: a population-based case-control study. Eur J Endocrinol. 2012b;167:483–490. doi: 10.1530/EJE-12-0356. [DOI] [PubMed] [Google Scholar]
  8. Carmichael SL, Ma C, Rasmussen SA, Honein MA, Lammer EJ, Shaw GM. Craniosynostosis and maternal smoking. Birth Defects Res A Clin Mol Teratol. 2008;82:78–85. doi: 10.1002/bdra.20426. [DOI] [PubMed] [Google Scholar]
  9. Carmichael SL, Shaw GM, Laurent C, Olney RS, Lammer EJ. Maternal reproductive and demographic characteristics as risk factors for hypospadias. Paediatr Perinat Epidemiol. 2007;21:210–218. doi: 10.1111/j.1365-3016.2007.00809.x. [DOI] [PubMed] [Google Scholar]
  10. Casey BM, Dashe JS, Wells CE, McIntire DD, Leveno KJ, Cunningham FG. Subclinical hyperthyroidism and pregnancy outcomes. Obstet Gynecol. 2006;107(2 Pt 1):337–341. doi: 10.1097/01.AOG.0000197991.64246.9a. [DOI] [PubMed] [Google Scholar]
  11. Chen CH, Xirasagar S, Lin CC, Wang LH, Kou YR, Lin HC. Risk of adverse perinatal outcomes with antithyroid treatment during pregnancy: a nationwide population-based study. Bjog. 2011;118:1365–1373. doi: 10.1111/j.1471-0528.2011.03019.x. [DOI] [PubMed] [Google Scholar]
  12. Cogswell ME, Bitsko RH, Anderka M, Caton AR, Feldkamp ML, Hockett Sherlock SM, Meyer RE, Ramadhani T, Robbins JM, Shaw GM, Mathews TJ, Royle M, Reefhuis J. Control selection and participation in an ongoing, population-based, case-control study of birth defects: the National Birth Defects Prevention Study. Am J Epidemiol. 2009;170:975–985. doi: 10.1093/aje/kwp226. [DOI] [PubMed] [Google Scholar]
  13. Cove DH, Johnston P. Fetal hyperthyroidism: experience of treatment in four siblings. Lancet. 1985;1:430–432. doi: 10.1016/s0140-6736(85)91148-1. [DOI] [PubMed] [Google Scholar]
  14. Daneman D, Howard NJ. Neonatal thyrotoxicosis: intellectual impairment and craniosynostosis in later years. J Pediatr. 1980;97:257–259. doi: 10.1016/s0022-3476(80)80487-2. [DOI] [PubMed] [Google Scholar]
  15. De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, Eastman CJ, Lazarus JH, Luton D, Mandel SJ, Mestman J, Rovet J, Sullivan S. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97:2543–2565. doi: 10.1210/jc.2011-2803. [DOI] [PubMed] [Google Scholar]
  16. English PB, Goldberg DE, Wolff C, Smith D. Parental and birth characteristics in relation to testicular cancer risk among males born between 1960 and 1995 in California (United States) Cancer Causes Control. 2003;14:815–825. doi: 10.1023/b:caco.0000003812.53344.48. [DOI] [PubMed] [Google Scholar]
  17. Glinoer D. The systematic screening and management of hypothyroidism and hyperthyroidism during pregnancy. Trends Endocrinol Metab. 1998;9:403–411. doi: 10.1016/s1043-2760(98)00095-2. [DOI] [PubMed] [Google Scholar]
  18. Haddow JE, Cleary-Goldman J, McClain MR, Palomaki GE, Neveux LM, Lambert-Messerlian G, Canick JA, Malone FD, Porter TF, Nyberg DA, Bernstein PS, D’Alton ME. Thyroperoxidase and thyroglobulin antibodies in early pregnancy and preterm delivery. Obstet Gynecol. 2010;116:58–62. doi: 10.1097/AOG.0b013e3181e10b30. [DOI] [PubMed] [Google Scholar]
  19. Hashmi SS, Canfield MA, Marengo L, Moffitt KB, Belmont JW, Freedenberg D, Tanksley SM, Lupo PJ. The association between neonatal thyroxine and craniosynostosis, Texas, 2004–2007. Birth Defects Res A Clin Mol Teratol. 2012;94:1004–1009. doi: 10.1002/bdra.23077. [DOI] [PubMed] [Google Scholar]
  20. He X, Wang P, Wang Z, He X, Xu D, Wang B. Thyroid antibodies and risk of preterm delivery: a meta-analysis of prospective cohort studies. Eur J Endocrinol. 2012;167:455–464. doi: 10.1530/EJE-12-0379. [DOI] [PubMed] [Google Scholar]
  21. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III) J Clin Endocrinol-Metab. 2002;87:489–499. doi: 10.1210/jcem.87.2.8182. [DOI] [PubMed] [Google Scholar]
  22. Honein MA, Rasmussen S. Further evidence for an association between maternal smoking and craniosynostosis. Teratol. 2000;62:145–146. doi: 10.1002/1096-9926(200009)62:3<145::AID-TERA1>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  23. Johnsonbaugh RE, Bryan RN, Hierlwimmer R, Georges LP. Premature craniosynostosis: A common complication of juvenile thyrotoxicosis. J Pediatr. 1978;93:188–191. doi: 10.1016/s0022-3476(78)80493-4. [DOI] [PubMed] [Google Scholar]
  24. Kallen B, Norstedt Wikner B. Maternal hypothyroidism in early pregnancy and infant structural congenital malformations. J Thyroid Res. 2014;2014:160780. doi: 10.1155/2014/160780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kallen K. Maternal smoking and craniosynostosis. Teratol. 1999;60:146–150. doi: 10.1002/(sici)1096-9926(199909)60:3<146::aid-tera10>3.3.co;2-v. [DOI] [PubMed] [Google Scholar]
  26. Khoury MJ, Becerra JE, d’Almada PJ. Maternal thyroid disease and risk of birth defects in offspring: a population-based case-control study. Paediatr Perinat Epidemiol. 1989;3:402–420. doi: 10.1111/j.1365-3016.1989.tb00528.x. [DOI] [PubMed] [Google Scholar]
  27. Knudsen N, Laurberg P, Rasmussen LB, Bulow I, Perrild H, Ovesen L, Jorgensen T. Small differences in thyroid function may be important for body mass index and the occurrence of obesity in the population. J Clin EndocrinolMetab. 2005;90:4019–4024. doi: 10.1210/jc.2004-2225. [DOI] [PubMed] [Google Scholar]
  28. Laurberg P, Nygaard B, Glinoer D, Grussendorf M, Orgiazzi J. Guidelines for TSH-receptor antibody measurements in pregnancy: results of an evidence-based symposium organized by the European Thyroid Association. EurJ Endocrinol. 1998;139:584–586. doi: 10.1530/eje.0.1390584. [DOI] [PubMed] [Google Scholar]
  29. Leonard CO, Ralston C, Carey JC, Morales L. Craniosynostosis and facial dysmorphism due to maternal Graves disease. Clin Res. 1987;35:225A. [Google Scholar]
  30. Mannisto T, Mendola P, Reddy U, Laughon SK. Neonatal outcomes and birth weight in pregnancies complicated by maternal thyroid disease. Am J Epidemiol. 2013;178:731–740. doi: 10.1093/aje/kwt031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Momotani N, Ito K, Hamada N, Ban Y, Nishikawa Y, Mimura T. Maternal hyperthyroidism and congenital malformation in the offspring. Clin Endocrinol (Oxf) 1984;20:695–700. doi: 10.1111/j.1365-2265.1984.tb00119.x. [DOI] [PubMed] [Google Scholar]
  32. Nishihara E, Fukata S, Hishinuma A, Kudo T, Ohye H, Ito M, Kubota S, Amino N, Kuma K, Miyauchi A. Sporadic congenital hyperthyroidism due to a germline mutation in the thyrotropin receptor gene (Leu 512 Gln) in a Japanese patient. Endocr J. 2006;53:735–740. doi: 10.1507/endocrj.k06-090. [DOI] [PubMed] [Google Scholar]
  33. Penfold JL, Simpson DA. Premature craniosynostosis-a complication of thyroid replacement therapy. J Pediatr. 1975;86:360–363. doi: 10.1016/s0022-3476(75)80963-2. [DOI] [PubMed] [Google Scholar]
  34. Rasmussen SA, Olney RS, Holmes LB, Lin AE, Keppler-Noreuil KM, Moore CA. Guidelines for case classification for the National Birth Defects Prevention Study. Birth Defects Res A Clin Mol Teratol. 2003;67:193–201. doi: 10.1002/bdra.10012. [DOI] [PubMed] [Google Scholar]
  35. Rasmussen SA, Yazdy MM, Carmichael SL, Jamieson DJ, Canfield MA, Honein MA. Maternal thyroid disease as a risk factor for craniosynostosis. Obstet Gynecol. 2007;110(2 Pt 1):369–377. doi: 10.1097/01.AOG.0000270157.88896.76. [DOI] [PubMed] [Google Scholar]
  36. Rasmussen SA, Yazdy MM, Frias JL, Honein MA. Priorities for public health research on craniosynostosis: summary and recommendations from a Centers for Disease Control and Prevention-sponsored meeting. Am J Med Genet A. 2008;146:149–158. doi: 10.1002/ajmg.a.32106. [DOI] [PubMed] [Google Scholar]
  37. Reefhuis J, Honein MA, Shaw GM, Romitti PA. 2003. Fertility treatments and craniosynostosis: California, Georgia, and Iowa, 1993–1997. Pediatrics. 2003;111:1163–1166. [PubMed] [Google Scholar]
  38. Richardson S, Browne ML, Rasmussen SA, Druschel CM, Sun L, Jabs EW, Romitti PA. Associations between periconceptional alcohol consumption and craniosynostosis, omphalocele, and gastroschisis. Birth Defects Res A Clin Mol Teratol. 2011;91:623–630. doi: 10.1002/bdra.20823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sanchez-Lara PA, Carmichael SL, Graham JM, Lammer EJ, Shaw GM, Ma C, Rasmussen SA. Fetal constraint as a potential risk factor for craniosynostosis. Am J Med Genet. 2010;152A:394–400. doi: 10.1002/ajmg.a.33246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Speltz ML, Kapp-Simon KA, Cunningham M, Marsh J, Dawson G. Single-suture craniosynostosis: a review of neurobehavioral research and theory. J Pediatr Psychol. 2004;29:651–668. doi: 10.1093/jpepsy/jsh068. [DOI] [PubMed] [Google Scholar]
  41. Stagnaro-Green A, Pearce E. Thyroid disorders in pregnancy. Nat Rev Endocrinol. 2012;8:650–658. doi: 10.1038/nrendo.2012.171. [DOI] [PubMed] [Google Scholar]
  42. Starr JR, Collett BR, Gaither R, Kapp-Simon KA, Cradock MM, Cunningham ML, Speltz ML. Multicenter study of neurodevelopment in 3-year-old children with and without single-suture craniosynostosis. Arch Pediatr Adolesc Med. 2012;166:536–542. doi: 10.1001/archpediatrics.2011.1800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Stevenson RE, Trent HE. Maternal hyperthyroidism and congenital craniosynostosis. Proc Greenwood Genet Center. 1990;9:3–6. [Google Scholar]
  44. van den Boogaard E, Vissenberg R, Land JA, van Wely M, van der Post JA, Goddijn M, Bisschop PH. Significance of (sub) clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update. 2011;17:605–619. doi: 10.1093/humupd/dmr024. [DOI] [PubMed] [Google Scholar]
  45. Wing DA, Millar LK, Koonings PP, Montoro MN, Mestman JH. A comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy. Am J Obstet Gynecol. 1994;170(1 Pt 1):90–95. doi: 10.1016/s0002-9378(94)70390-6. [DOI] [PubMed] [Google Scholar]
  46. Wu EL, Chien IC, Lin CH, Chou YJ, Chou P. Increased risk of hypothyroidism and hyperthyroidism in patients with major depressive disorder: a population-based study. J Psychosom Res. 2013;74:233–237. doi: 10.1016/j.jpsychores.2012.12.016. [DOI] [PubMed] [Google Scholar]
  47. Yoon PW, Rasmussen SA, Lynberg MC, Moore CA, Anderka M, Carmichael SL, Costa P, Druschel C, Hobbs CA, Romitti PA, Langlois PH, Edmonds LD. The National Birth Defects Prevention Study. Public Health Rep. 2001;116:32–40. doi: 10.1093/phr/116.S1.32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Yoshihara A, Noh J, Yamaguchi T, Ohye H, Sato S, Sekiya K, Kosuga Y, Suzuki M, Matsumoto M, Kunii Y, Watanabe N, Mukasa K, Ito K, Ito K. Treatment of graves’ disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation. J Clin Endocrinol Metab. 2012;97:2396–2403. doi: 10.1210/jc.2011-2860. [DOI] [PubMed] [Google Scholar]
  49. Zimmermann MB, Burgi H, Hurrell RF. Iron deficiency predicts poor maternal thyroid status during pregnancy. J Clin Endocrinol Metab. 2007;92:3436–3440. doi: 10.1210/jc.2007-1082. [DOI] [PubMed] [Google Scholar]

RESOURCES