Impact of adjusting for the reciprocal relationship between maternal weight and free thyroxine during early pregnancy

Abstract

Background: Among euthyroid pregnant women in a large clinical trial, free thyroxine (FT4) measurements below the 2.5th centile were associated with a 17 lb higher weight (2.9 kg/m(2)) than in the overall study population. We explore this relationship further.

Methods: Among 9351 women with second trimester thyrotropin (TSH) measurements between 1st and 98th centiles, we examine: (i) the weight/FT4 relationship; (ii) percentages of women in three weight categories at each FT4 decile; (iii) FT4 concentrations in three weight categories at each TSH decile; and (iv) impact of adjusting FT4 for weight--in the reference group and in 190 additional women with elevated TSH measurements.

Results: FT4 values decrease steadily as weight increases (p<0.0001 by ANOVA) among women in the reference group (TSH 0.05-3.8 IU/L). TSH follows no consistent pattern with weight. When stratified into weight tertiles, 48% of women at the lowest FT4 decile are heavy; the percentage decreases steadily to 22% at the highest FT4 decile. Median FT4 is lowest in heaviest women regardless of the TSH level. In the reference group, weight adjustment reduces overall variance by 2.9%. Fewer FT4 measurements are at either extreme (below the 5th FT4 centile: 4.8% before adjustment, 4.7% after adjustment; above the 95th FT4 centile: 5.0% and 4.7%, respectively). Adjustment places more light weight women and fewer heavy women below the 5th FT4 centile; the converse above the 95th centile. Between TSH 3.8 and 5 IU/L, the FT4 percentage below the 5th FT4 centile is not elevated (3.8% before adjustment, 3.1% after adjustment). Percentage of FT4 values above the 95th centile, however, is lower (1.5% before adjustment, 0.8% after adjustment). Above TSH 5 IU/L, 25% of women have FT4 values below the 5th FT4 centile; weight adjustment raises this to 30%; no FT4 values remain above the 95th FT4 centile.

Conclusions: During early pregnancy, TSH values are not associated with weight, unlike nonpregnant adults. Lower average FT4 values among heavy women at all TSH deciles partially explain interindividual differences in FT4 reference ranges. The continuous reciprocal relationship between weight and FT4 explains lower FT4 with higher weight. Weight adjustment refines FT4 interpretation.

FIG. 1.

The relationship between maternal weight and free thyroxine (FT4) and thyrotropin (TSH) concentrations at 15–20 weeks gestation. The X axis shows mean maternal weight at 20 lb intervals between 80 and 300 lb (and also at 317 lb). Open boxes (□) represent median FT4 values at each weight interval, expressed as multiples of the overall study population median (multiples of the median [MoM]). Samples for FT4 measurements were obtained between 15 and 20 weeks' gestation. The dotted line describes the best fit curve for the weight/FT4 relationship. Open circles (○) represent median TSH measurements obtained from the same samples. No consistent relationship with weight is apparent.

FIG. 2.

(a) Proportional representation of three categories of maternal weight within FT4 deciles 1–10. The 9351 second-trimester women with TSH measurements between the 1st and 98th centiles are stratified into tertiles, according to weight (Table 2). Open diamonds (⋄) represent Light women, closed circles (●) Medium weight women, and open triangles (▵) Heavy women. The x-axis shows FT4 intervals by decile, while the y-axis shows percentages of women in the three weight categories within each FT4 decile. In the absence of a relationship between FT4 and weight, roughly a third of women in each weight category should be represented at all deciles. Horizontal lines at 28% and 37% denote expected range of fluctuation in the absence of a weight relationship. (b) Proportional representation of three categories of maternal weight within FT4 deciles 1–10 following weight adjustment of FT4.

FIG. 3.

Proportional representation of three categories of maternal weight within TSH deciles 1–10. This is similar to Figure 2a, except that TSH deciles are shown on the x-axis. Women in the three weight categories are represented proportionally at all TSH deciles, indicating lack of a relationship with weight.

FIG. 4.

(a) Median FT4 concentrations at three categories of maternal weight within TSH deciles 1–10 between 15 and 20 weeks gestation. The 9351 women with TSH measurements between the 1st and 98th centiles are stratified into tertiles, according to weight (Table 2). Open diamonds (⋄) represent Light women, closed circles (●) Medium weight women, and open triangles (▵) Heavy women. The x-axis shows TSH intervals by decile, while the y-axis shows median FT4 concentrations for each weight category within each TSH decile. At all deciles, relative FT4 concentrations are lowest among Heavy women. (b) Median FT4 concentrations at three categories of maternal weight within TSH deciles 1–10 between 15 and 20 weeks gestation following weight adjustment of FT4.