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Meta-Analysis
. 2022 Sep 28;107(10):2925-2933.
doi: 10.1210/clinem/dgac425.

TSH and FT4 Reference Intervals in Pregnancy: A Systematic Review and Individual Participant Data Meta-Analysis

Joris A J Osinga  1   2 , Arash Derakhshan  1   2 , Glenn E Palomaki  3 , Ghalia Ashoor  4 , Tuija Männistö  5 , Spyridoula Maraka  6   7   8 , Liangmiao Chen  9 , Sofie Bliddal  10 , Xuemian Lu  9 , Peter N Taylor  11 , Tanja G M Vrijkotte  12 , Fang-Biao Tao  13 , Suzanne J Brown  14 , Farkhanda Ghafoor  15 , Kris Poppe  16 , Flora Veltri  16 , Lida Chatzi  17 , Bijay Vaidya  18 , Maarten A C Broeren  19 , Beverley M Shields  20 , Sachiko Itoh  21 , Lorena Mosso  22 , Polina V Popova  23   24   25 , Anna D Anopova  23 , Reiko Kishi  21 , Ashraf Aminorroaya  26 , Maryam Kianpour  26 , Abel López-Bermejo  27   28 , Emily Oken  29 , Amna Pirzada  30 , Marina Vafeiadi  31 , Wichor M Bramer  32 , Eila Suvanto  33 , Jun Yoshinaga  34 , Kun Huang  35 , Judit Bassols  36 , Laura Boucai  37 , Ulla Feldt-Rasmussen  10 , Elena N Grineva  23 , Elizabeth N Pearce  38 , Erik K Alexander  39 , Victor J M Pop  40 , Scott M Nelson  41 , John P Walsh  14   42 , Robin P Peeters  1   2 , Layal Chaker  1   2   43 , Kypros H Nicolaides  44 , Mary E D'Alton  45 , Tim I M Korevaar  1   2
Affiliations
Meta-Analysis

TSH and FT4 Reference Intervals in Pregnancy: A Systematic Review and Individual Participant Data Meta-Analysis

Joris A J Osinga et al. J Clin Endocrinol Metab. .

Abstract

Context: Interpretation of thyroid function tests during pregnancy is limited by the generalizability of reference intervals between cohorts due to inconsistent methodology.

Objective: (1) To provide an overview of published reference intervals for thyrotropin (TSH) and free thyroxine (FT4) in pregnancy, (2) to assess the consequences of common methodological between-study differences by combining raw data from different cohorts.

Methods: (1) Ovid MEDLINE, EMBASE, and Web of Science were searched until December 12, 2021. Studies were assessed in duplicate. (2) The individual participant data (IPD) meta-analysis was performed in participating cohorts in the Consortium on Thyroid and Pregnancy.

Results: (1) Large between-study methodological differences were identified, 11 of 102 included studies were in accordance with current guidelines; (2) 22 cohorts involving 63 198 participants were included in the meta-analysis. Not excluding thyroid peroxidase antibody-positive participants led to a rise in the upper limits of TSH in all cohorts, especially in the first (mean +17.4%; range +1.6 to +30.3%) and second trimester (mean +9.8%; range +0.6 to +32.3%). The use of the 95th percentile led to considerable changes in upper limits, varying from -10.8% to -21.8% for TSH and -1.2% to -13.2% for FT4. All other additional exclusion criteria changed reference interval cut-offs by a maximum of 3.5%. Applying these findings to the 102 studies included in the systematic review, 48 studies could be used in a clinical setting.

Conclusion: We provide an overview of clinically relevant reference intervals for TSH and FT4 in pregnancy. The results of the meta-analysis indicate that future studies can adopt a simplified study setup without additional exclusion criteria.

Keywords: free thyroxine (FT4); pregnancy; reference values; thyroid; thyrotropin (TSH).

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Figures

Figure 1.
Figure 1.
Study selection flowchart.
Figure 2.
Figure 2.
Overview studies systematic review trimester 1. *Reference intervals calculated with individual participant data in consortium. ○, iodine sufficiency; ▽, mild-to-moderate iodine deficiency; △, excessive iodine status. Reference intervals calculated in cohorts with fluctuating or excessive iodine status are listed in gray.
Figure 3.
Figure 3.
Overview studies systematic review trimester 2. *Reference intervals calculated with individual participant data in consortium. ○, iodine sufficiency; ▽, mild-to-moderate iodine deficiency; △, excessive iodine status. Reference intervals calculated in cohorts with fluctuating or excessive iodine status are listed in gray.
Figure 4.
Figure 4.
Overview studies systematic review trimester 3. *Reference intervals calculated in individual participant data in consortium; ○, iodine sufficiency; ▽, mild-to-moderate iodine deficiency.
Figure 5.
Figure 5.
Results meta-analyses trimester 1.  1Defined as the weighted average change in reference limits across cohorts. 2Calculated using 2.5th to 97.5th percentiles, excluding prepregnancy thyroid disease, use of thyroid hormone–altering medication, and TPOAb positivity; the total number of participants in subgroups differs based on availability of data on additional exclusion criteria. 3Defined as prepregnancy diabetes mellitus. 4Defined as BMI > 30 kg/m2 at time of intake. 5Pregnancy by in vitro fertilization. 6Defined as gestational diabetes, gestational hypertension, pre-eclampsia, preterm birth, and/or small for gestational age.
Figure 6.
Figure 6.
Results meta-analyses trimester 2.  1Defined as the weighted average change in reference limits across cohorts. 2Calculated using 2.5th to 97.5th percentiles, excluding pre-pregnancy thyroid disease, use of thyroid hormone altering medication, and TPOAb-positivity; the total number of participants in subgroups differs based on availability of data on additional exclusion criteria. 3Defined as prepregnancy diabetes mellitus. 4Defined as BMI >30 kg/m2 at time of intake. 5Pregnancy by in vitro fertilization. 6Defined as gestational diabetes, gestational hypertension, pre-eclampsia, preterm birth, and/or small for gestational age.
Figure 7.
Figure 7.
Results meta-analyses trimester 3.  1Defined as the weighted average change in reference limits across cohorts. 2Calculated using 2.5th to 97.5th percentiles, excluding prepregnancy thyroid disease, use of thyroid hormone altering medication, and TPOAb-positivity; the total number of participants in subgroups differs based on availability of data on additional exclusion criteria. 3Defined as prepregnancy diabetes mellitus. 4Defined as BMI >30 kg/m2 at time of intake. 5Pregnancy by in vitro fertilization. 6Defined as gestational diabetes, gestational hypertension, pre-eclampsia, preterm birth, and/or small for gestational age.
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