DOI: https://doi.org/10.21203/rs.3.rs-219858/v1
Neonatal screening for congenital primary hypothyroidism (CH) may not distinguish between transient (TCH) and permanent dysfunction (PCH), causing potential overtreatment and concerns in affected families. To specify the indication for interruption of therapy we analysed the German registry "HypoDok" for infants with CH, which oversees 1,625 patients from 49 participating centres in Germany and Austria from 1997 until today. 357 Patients with a thyroid gland in loco typico were identified and retrospectively grouped according to cessation (TCH n=24) or continuation (PCH n=333) of L-Thyroxine (L-T4) treatment at 2 years of age. The receiver operating characteristic (ROC) analysis was performed to identify cut-offs predicting TCH by screening TSH concentrations and L-T4 dosages. Gestational ages, birth weights and prevalence of associated malformations were comparable in both groups.
The cut-off screening TSH concentration was 73 mU/L. The cut-off daily L-T4 dosage at 1 year was 3.1 µg/kg (90% sensitivity, 63% specificity; 36 µg/d) and at 2 years of age 2.95 µg/kg (91% sensitivity, 59% specificity; 40 µg/d). At 2 years of age, specificity (71%) increased when these both parameters were considered together.
Conclusion: The decision to continue or cease L-T4 treatment at 2 years of age in CH patients diagnosed in neonatal screening may be based on their screening TSH concentrations and individual L-T4 dosages at 1 and 2 years of age. Thus, TCH and PCH may be distinguished; overtreatment avoided, and affected families reassured.
Table 1
Demographic characteristics and medical history of patients at diagnosis: patients were grouped as permanent CH (PCH; n=333) or transient CH (TCH; n=24). Variables are presented as median and interquartile range (table 1A) or frequency of occurrence (%; table 1B)
|
Table 1A |
|
|
PCH |
|
|
TCH |
|
||
|
Variable |
n |
Median |
Interquartile range |
n |
Median |
Interquartile range |
p |
||
|
Weeks of gestation |
333 |
40 |
38-41 |
24 |
40 |
37-40 |
1.0 |
||
|
Birth weight (g) |
325 |
3420 |
3060-3800 |
22 |
3380 |
2920-3850 |
1.0 |
||
|
APGAR-Score |
326 |
10 |
7-10 |
22 |
10 |
9-10 |
1.0 |
||
|
BMI (kg/m2) after 2 yrs. |
301 |
16.6 |
15.6-17.5 |
22 |
16 |
14.7-16.5 |
0.8 |
||
|
BMI-SDS after 2 yrs. |
301 |
0.4 |
0.3-1.0 |
22 |
0.0 |
-1.1-0.4 |
0.7 |
||
|
Height-SDS after 2 yrs. |
301 |
0.1 |
-0.6-0.8 |
23 |
0.0 |
-0.6-0.5 |
1.0 |
||
|
Table 1B |
PCH |
TCH |
|||||||
|
Variable |
n |
Prevalence (%) |
|
n |
Prevalence (%) |
|
p |
||
|
Weeks of gestation < 36 |
322 |
5.6 |
- |
24 |
12.5 |
- |
1.0 |
||
|
Male gender |
333 |
35.1 |
- |
24 |
50 |
- |
1.0 |
||
|
Trisomy 21 |
333 |
1.2 |
- |
24 |
4.2 |
- |
1.0 |
||
|
Dopamine therapy |
333 |
0.9 |
- |
24 |
8.3 |
- |
0.07 |
||
|
ATD in pregnancy |
101 |
2 |
- |
11 |
18.2 |
- |
0.1 |
||
|
L-T4 withdrawal period |
211 |
52.6 |
- |
24 |
100 |
- |
<0.01 |
||
|
L-T4 withdrawal period a./o. L-T4dosage increase |
333 |
95.2 |
- |
24 |
100 |
- |
1.0 |
||
|
Developmental test: normal |
141 |
89 |
- |
8 |
100 |
- |
1.0 |
||
Table 2
Screening TSH (mU/L), confirmation serum TSH (µU/ml), and serum fT4 (ng/ml), dosages of L-T4 at diagnosis, at the age of 1 and 2 years in patients with permanent CH (PCH, n=273) and transient CH (TCH, n=23). Data are given as median with interquartile range, p<0.05 was considered significantly different by chi χ2-test.
|
|
PCH |
TCH |
|
||||
|
Variable |
n |
Median |
Interquartile range |
n |
Median |
Interquartile range |
p |
|
Screening TSH (mU/L) |
333 |
150 |
62-237 |
24 |
55.8 |
32.5-136 |
0.06 |
|
Confirmation TSH (µU/ml) |
257 |
118 |
62-227 |
23 |
100 |
42-169 |
1.0 |
|
Serum fT4 (ng/dl) |
275 |
1.16 |
0.5-2.33 |
21 |
0.96 |
0,4-1.4 |
1.0 |
|
L-T4 dose at diagnosis (µg) |
333 |
50 |
44-50 |
24 |
50 |
29-50 |
1.0 |
|
L-T4 dose at diagnosis (µg/kg) |
328 |
13.2 |
10-15 |
23 |
12.5 |
10-14 |
1.0 |
|
L-T4 dose after 6 month (µg) |
157 |
38 |
30-50 |
13 |
25 |
25-38 |
0.4 |
|
L-T4 dose after 6 month (µg/kg) |
153 |
4.74 |
3.8-5.76 |
13 |
4.47 |
3.25-5 |
1.0 |
|
L-T4 dose after 1 year (µg) |
307 |
45 |
38-50 |
24 |
30 |
25-42 |
<0.01 |
|
L-T4 dose after 1 year (µg/kg) |
306 |
4.52 |
3.8-5.2 |
24 |
2.96 |
2.3-4.6 |
<0.01 |
|
L-T4 dose after 2 years (µg) |
302 |
50 |
44-60 |
23 |
37 |
25-50 |
<0.01 |
|
L-T4 dose after 2 years (µg/kg) |
301 |
4.03 |
3.6-4.74 |
22 |
2.5 |
1.95-3.66 |
<0.01 |
Table 3
Subgroup analyses in patients with screening-TSH<73mU/L (n=109) Screening TSH (mU/L) at the age of 1 and 2 years in patients with permanent CH (PCH, n=94) and transient CH (TCH, n=15).
|
|
PCH |
TCH |
|
||||
|
Variable |
n |
Median |
Interquartile range |
n |
Median |
Interquartile range |
p |
|
L-T4 dose after 6 month (µg) |
45 |
35 |
25-38 |
10 |
25 |
25-35 |
0.35 |
|
L-T4 dose after 6 month (µg/kg) |
45 |
4.1 |
3.4-5.4 |
10 |
3.6 |
3.2-4.5 |
0.5 |
|
L-T4 dose after 1 year (µg) |
86 |
40 |
37-50 |
15 |
25 |
25-44 |
0.02 |
|
L-T4 dose after 1 year (µg/kg) |
86 |
4.4 |
3.5-5.2 |
15 |
2.8 |
2.3-4.9 |
0.04 |
|
L-T4 dose after 2 year (µg) |
82 |
50 |
38-50 |
14 |
25 |
25-40 |
<0.01 |
|
L-T4 dose after 2 year (µg/kg) |
82 |
3.9 |
3.2-4.3 |
14 |
2.3 |
1.95-3.7 |
0.01 |
|
L-T4withdrawal period a./o. L-T4 dosage increase |
94 |
94 |
- |
15 |
100 |
- |
0.5 |
Table 3A/B
Cut-off-concentrations predicting TCH by screening TSH, of dosages of L-T4 at the ages of 1 and 2 years (3A), Subgroup analyses in patients with screening-TSH<73mU/L (PCH n=94, TCH n=15) (3B).
|
Table 3A |
Cut-off |
Sensitivity % |
Specificity % |
|
Screening TSH |
73mU/L |
72 |
63 |
|
L-T4 after 1 y. µg/kg/d |
3.1 |
90 |
63 |
|
µg/d |
36 |
85 |
54 |
|
L-T4 after 1 y. µg/kg/d |
2.0 |
99 |
4 |
|
|
20 |
99 |
8 |
|
L-T4 after 1 y. µg/kg/d |
6.3 |
4 |
96 |
|
µg/d |
60 |
10 |
96 |
|
L-T4 after 2 y. µg/kg/d |
2.95 |
91 |
59 |
|
µg/d |
40 |
84 |
65 |
|
L-T4 after 2 y. µg/kg/d |
2.0 |
99 |
27 |
|
µg/d |
25 |
100 |
13 |
|
L-T4 after 2 y. µg/kg/d |
5.0 |
18 |
96 |
|
µg/d |
55 |
31 |
96 |
|
Table 3B |
Cut-off |
Sensitivity % |
Specificity% |
|
L-T4 after 1 y. µg/kg/d |
2.9 |
85 |
60 |
|
µg/d |
27.5 |
86 |
60 |
|
L-T4 after 1 y. µg/kg/d |
2.2 |
99 |
13 |
|
µg/d |
20 |
99 |
7 |
|
L-T4 after 1 y. µg/kg/d |
6.6 |
2 |
93 |
|
µg/d |
60 |
8 |
100 |
|
L-T4 after 2 y. µg/kg/d |
2.96 |
81 |
71 |
|
|
38 |
83 |
64 |
|
L-T4 after 2 y. µg/kg/d |
1.85 |
99 |
21 |
|
µg/d |
25 |
99 |
7 |
|
L-T4 after 2 y. µg/kg/d |
6.3 |
11 |
100 |
|
µg/d |
72.5 |
18 |
100 |