OBJECTIVE: To estimate if there is a relationship between subclinical thyroid disease and gestational diabetes.
METHODS: Between November 2000 and April 2003, serum thyrotropin screening was performed on all women who presented for prenatal care. Women identified with abnormal thyrotropin had a serum free thyroxine reflexively determined. Those women with abnormal serum free thyroxine values were referred for further evaluation and excluded from further analysis. For this analysis, normal thyrotropin values were those between the 2.5th and 97.5th percentiles (0.03–4.13 milliunits/L) not corrected for gestational age and serum free thyroxine were considered normal if they ranged from 0.9 to 2.0 mg/dL. Women with an elevated serum thyrotropin but a normal serum free thyroxine were designated to have subclinical hypothyroidism and those with a low thyrotropin and a normal serum free thyroxine level were designated to have subclinical hyperthyroidism. Euthyroid women had both normal thyrotropin and normal serum free thyroxine values. The incidence of gestational diabetes was compared among these three groups.
RESULTS: Of the 24,883 women included in the study, 23,771 (95.5%) were euthyroid, 584 (2.3%) had subclinical hyperthyroidism, and 528 (2%) had subclinical hypothyroidism. The likelihood of gestational diabetes increased with thyrotropin level (P=.002). For example, when a pregnant Hispanic woman of average age and weight was used, the predicted percent of gestational diabetes increased from 1.9% to 4.9% as thyrotropin increased from 0.001 to 10 milliunits/L (P=.001).
CONCLUSION: The risk of developing gestational diabetes increases with thyrotropin level. This supports a relationship between subclinical hypothyroidism and diabetes diagnosed during pregnancy.
LEVEL OF EVIDENCE: III
The risk of gestational diabetes in women with normal serum free thyroxine levels increases with thyrotropin level.
From the Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas.
Presented at the 31st Annual Society for Maternal-Fetal Medicine Meeting, February 7–12, 2011, San Francisco, California.
Corresponding author: Carmen M. Tudela, MD, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9032; e-mail: firstname.lastname@example.org.
Financial Disclosure Reimbursement has been received by Dr. Cunningham's department of Obstetrics & Gynecology of the University of Texas Southwestern Medical Center from the McGraw-Hill Publishing Co. to offset expenses for preparation of various textbooks. The reimbursement is for secretarial time, equipment use, and office supplies expended in the revision of the 24th edition of Williams Obstetrics and the 2nd edition of Williams Gynecology as well as handbooks, manuals, study guides, and online derivatives. In addition, Dr. Cunningham receives royalties for these textbooks as well as for their earlier editions and their derivative publications. The other authors did not report any potential conflicts of interest.
Overtly abnormal amounts of thyroid hormones—either excessive because of Graves' thyrotoxicosis or deficient because of hypothyroidism—can have profound effects on glucose metabolism and insulin secretion. The resulting increased insulin resistance, glucose intolerance, and dyslipidemia are usually reversible when normal thyroid hormone levels are restored.1–3 Both subclinical hyperthyroidism and hypothyroidism are reported to have similar but correspondingly less marked metabolic effects in nonpregnant women.4,5 In pregnant women, however, virtually nothing is known regarding possible metabolic changes with either type of subclinical thyroid dysfunction.
It is well known that marked insulin resistance progressively increases with gestational age during pregnancy.6 Because of the similar effects of thyroid hormone and pregnancy on glucose metabolism, it seems reasonable to posit that women with either abnormally high or low levels of thyroid hormones would be more likely to develop gestational diabetes. Untreated overt hyperthyroidism or hypothyroidism in pregnant women is uncommon, and none of the reports of such pregnancies described any effects on glucose metabolism.7–10 Conversely, because subclinical thyroid dysfunction in pregnancy is relatively common and usually not treated, there recently has been a number of population-based studies of subclinical thyroid dysfunction during pregnancy. Two of the largest studies reported conflicting results concerning any associations with gestational diabetes.11,12 Because of this, we designed the currently reported secondary analysis of a larger cohort of women who presented for prenatal care at all gestational ages to further estimate any effects that subclinical thyroid dysfunction may have on the incidence of gestational diabetes.
MATERIALS AND METHODS
Excess serum obtained for prenatal serological screening, from November 1, 2000, to April 14, 2003, was delivered each weekday to our immunochemistry research laboratory for thyroid studies. The protocol for this study has been approved by the University of Texas Southwestern Medical Center institutional review board committee and found to be minimal risk research. Using a chemiluminescent assay, serum concentrations were determined for thyrotropin and serum free thyroxine (T4). Women identified to have abnormal thyrotropin levels had a serum free T4 reflexively determined, and, if it was either abnormally high or low, they were contacted and referred to an obstetrical complications clinic for further evaluation and possible treatment. These women were excluded from further study. Subsequent to this prospective evaluation, serum samples in women who presented for prenatal care in the first half of pregnancy were retrieved and serum free T4 levels were measured. The details of this process and assays have been previously described.11,13,14
For the purposes of the current study, normal values were considered to be those that comprised the range from the 2.5th to 97.5th percentiles, not corrected for gestational age, for the study population. For thyrotropin, these were 0.03–4.13 milliunits/L and for serum free T4, these ranged from 0.9 to 2.0 ng/dL. Using these thresholds, all women with abnormal thyrotropin values had reflexive serum free T4 values determined regardless of gestational age. Women screened and delivered of singleton neonates weighing 500 g or more at Parkland Hospital and without evidence of overt thyroid dysfunction were included in this analysis. Women with serum thyrotropin and serum free T4 values within the normal range were considered to be euthyroid. Those with an abnormally low thyrotropin but normal serum free T4 level were classified as having subclinical hyperthyroidism. Conversely, women with an abnormally high thyrotropin but a normal serum free T4 level were classified as having subclinical hypothyroidism.
Pregnancy outcomes were retrieved from a computerized perinatal database that has been previously described.11,13,14 These data are routinely entered for all women at the time of their delivery at Parkland Hospital. For this study, the incidence of gestational diabetes was compared for the three cohorts described. Gestational diabetes was defined as diabetes diagnosed during pregnancy regardless of the gestational age at diagnosis. This included both women with gestational diabetes treated with diet and those with gestational diabetes treated with insulin. The diagnosis of gestational diabetes was made using a 1-hour 50-g screening test and a 100-g 3-hour tolerance test. If two or more plasma levels using the National Diabetes Data Group criteria, and accepted by the American Congress of Obstetricians and Gynecologists, were abnormal, then the diagnosis of gestational diabetes was made.15
Pearson χ2, Armitage test for trend, analysis of variance with Dunnett's test for multiple comparisons to a control group, and Student's t test were used for group comparisons. Logistic regression was applied to examine the significance for selected pregnancy outcomes adjusted for maternal age, race, parity, and weight. The Hosmer-Lemeshow statistic was used to examine the goodness of fit for the logistic regression model. To further investigate the relationship between thyrotropin and the likelihood of gestational diabetes, we incorporated a logistic regression model including thyrotropin level as a continuous variable. We used the logarithm of thyrotropin as an independent predictor of gestational diabetes and adjusted for maternal age and weight as continuous measures through a cubic smoothing splines with knots at 5th, 25th, 50th, 75th, and 95th percentiles as well as categorical variables of race and parity. Statistical computations were performed with SAS 9. Two-sided P<.05 were judged statistically significant.
During the 30-month study, a total of 24,883 women were delivered of a singleton fetus weighing more than 500 g and are included in this study. Of these, 23,771 (95.5%) had thyrotropin values within the normal range and were considered euthyroid; 528 (2.1%) had a thyrotropin level greater than 4.13 milliunits/L along with a normal serum free T4 level and therefore met criteria for subclinical hypothyroidism; and the remaining 584 (2.3%) had a thyrotropin level less than 0.03 milliunits/L along with a normal serum free T4 level meeting criteria for subclinical hyperthyroidism.
Maternal demographics of the three cohorts are shown in Table 1. Women with either subclinical hyperthyroidism or hypothyroidism are compared with euthyroid women. Those with subclinical hyperthyroidism were more likely to be African American or “other” ethnicity. Also, on average, women with subclinical hyperthyroidism weighed less than women in the other two cohorts. Conversely, women with subclinical hypothyroidism were less likely to be African American and, as a group, were significantly older than the other study groups.
As shown in Figure 1, the incidence of gestational diabetes is compared between the three study groups. In general, as screening thyrotropin level increased, the likelihood of diabetes complicating pregnancy also increased (P=.002). For example, 2.2% of women identified with subclinical hyperthyroidism had gestational diabetes as compared with 4.2% of euthyroid women and 6.3% of women with subclinical hypothyroidism. As shown in Figure 2, after adjustment for maternal age, weight, race, parity, and gestational age at screening, the risk for gestational diabetes in women with subclinical hyperthyroidism remained significantly lower (P=.022). However, the increased risk of gestational diabetes in women with subclinical hypothyroidism was no longer significant (P=.056).
To further investigate the relationship between thyrotropin level and the likelihood of gestational diabetes, we incorporated a logistic regression model including thyrotropin level as a continuous measure. After adjusting for maternal factors of age, weight, race, and parity, thyrotropin was a significant predictor of gestational diabetes (P=.001). There was no indication of a lack of fit for this model as indicated by the Hosmer-Lemeshow test (P=.31). To illustrate this effect, we provide Figure 3 with selected covariable levels of a 25-year-old nulliparous, Hispanic woman weighing 175 pounds. For this example, the probability of gestational diabetes complicating pregnancy increased from 1.9% if the thyrotropin was 0.001 milliunits/L to 4.9% if the thyrotropin was 10 milliunits/L in such women (P=.001). Because this is the result of the logistic regression model, this is representative of other levels of the covariates but with the likelihood of gestational diabetes increasing with thyrotropin.
This report is another in a series in which we further describe the relationships between a number of thyroid-associated analytes and pregnancies in nearly 25,000 women.11,13,14,16–18 This secondary analysis was designed to elucidate previously reported associations between subclinical thyroid dysfunction in these women and their risks for developing gestational diabetes during the same pregnancy. Our findings now presented indicate that there are two reasons to support such a relationship. The first and strongest of these is the direct correlation between increasing serum thyrotropin concentrations and the probability of gestational diabetes as depicted in Figure 3. Importantly, this association remained significant after adjustment for maternal age, race, and weight, factors known to have profound effects on both the incidence of subclinical hypothyroidism as well as gestational diabetes. The second supportive finding is that women with subclinical hypothyroidism were at significantly greater risk for gestational diabetes when compared with the cohort of euthyroid women (Fig. 1). Unlike the first observation, however, the significance of this finding was now of borderline significance after we adjusted for the same risk confounders (P=.056).
There are previous reports that reinforce a positive relationship between subclinical hypothyroidism and gestational diabetes. The biological plausibility of our findings finds support from studies in nonpregnant adults that describe the metabolic actions of T4 and insulin. Some of these observations are that both overt and subclinical hypothyroidism cause significantly increased insulin resistance.4,19–21 In fact, this was shown to induce abnormal glucose tolerance test values remarkably similar to those characteristic of normal pregnancy and also as a result of insulin resistance.4,6 When taken together, it seems reasonable to speculate that pregnant women with subclinical hypothyroidism have further amplified insulin resistance and thus an increased risk for gestational diabetes.
There are other findings that argue against the likelihood that subclinical hypothyroidism is related to an increased risk for gestational diabetes. First, as discussed previously, the relationship between subclinical hypothyroidism and gestational diabetes was only of borderline significance after adjustment for age, weight, race, parity, and gestational age (P=.056). A second argument is that such an association was not found by Cleary-Goldman et al12 in a similar study of thyroid analytes in more than 10,000 pregnant women One explanation for this is that one-third of women in our cohort with subclinical hypothyroidism were found to have abnormally elevated antithyroid antibodies, more than twice that of 15% in the Cleary-Goldman cohort.12,16 This observation is important in light of findings of Mannisto et al22 who reported that pregnant women with thyroid disease and abnormally high thyroid antibody levels were at inordinately high risk for later developing noninsulin-dependent diabetes mellitus. Also possibly related to the ethnic differences, Hispanic women are at much higher risk for gestational diabetes when compared with white women.23
Another interesting and unexpected finding was that women with subclinical hyperthyroidism had a significantly lower risk for developing gestational diabetes when compared with euthyroid women. This observation has not been reported in the previously cited population studies.12,14,22 This observation is counterintuitive because insulin resistance is a feature of hyperthyroidism, both overt and subclinical.5,24 Moreover, diabetes has a consistently positive association in patients with overt hyperthyroidism25–27 At this time, we can offer no biological explanation for the significant association between this possible “protective” effect of subclinical hyperthyroidism against gestational diabetes and await any confirmatory studies.
In summary, findings now reported include a consistent significant relationship between increasing serum thyrotropin levels, in women, with normal serum free T4 concentrations and a correspondingly increased risk for gestational diabetes in the same pregnancy. These findings suggest, albeit less strongly, that women with subclinical hypothyroidism are at higher risk for gestational diabetes when compared with euthyroid women. Taken together with reports that overt or subclinical hypothyroidism results in increased peripheral insulin resistance, it is biologically plausible that these effects magnify normal pregnancy-induced insulin resistance.4,6 At this time, these findings should not be considered an indication for routine prenatal serum thyroid-analyte screening nor for targeted screening in women identified to have gestational diabetes.
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