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Accurate interpretation of thyroid dysfunction during pregnancy: should we continue to use published guidelines instead of population-based gestation-specific reference intervals for the thyroid-stimulating hormone (TSH)?

Turkal, Rana, Turan, Cem Armağan, Elbasan, Onur, Aytan, Serenay, Çakmak, Burcu, Gözaydınoğlu, Büşra, Takır, Duygu Ceyda, Ünlü, Ozan, Bahramzada, Günel, Tekin, Ahmet Faruk, Çevlik, Tülay, Büyükbayrak, Esra Esim, Şirikçi, Önder, Gözü, Hülya, Haklar, Goncagül·2022·BMC Pregnancy and Childbirth
DOI 10.1186/s12884-022-04608-zPMC PMC8973886
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Abstract

Background: Considering the changes in thyroid physiology associated with pregnancy and poor outcomes related to abnormal maternal thyroid function, international guidelines recommend using population-based trimester-specific reference intervals (RIs) for thyroid testing. If these RIs are not available in the laboratory, implementing recommended fixed cut-off values globally is still controversial. To address this issue, we aimed to establish appropriate RI of thyroid-stimulating hormone (TSH) in pregnant Turkish women for our laboratory and compare the prevalence of thyroid dysfunction based on the established and recommended criteria. Methods: Of 2638 pregnant women, 1777 women followed in the obstetric outpatient were enrolled in the reference interval study after applying exclusion criteria related to medical and prenatal history. A retrospective study was conducted by collecting data from July 2016 to March 2019. Serum TSH was measured by UniCel DxI 800 Immunoassay System (Beckman Coulter Inc., Brea, CA, USA). The study design relied on two approaches in order to classify pregnant women: trimester-specific and subgroup-specific; the latter involved dividing each trimester into two subgroups: T1 a, T1 b, T2 a, T2 b, T3 a, T3 b. The lower and upper limits of the RIs were derived by the parametric method after normalizing the data distribution using the modified Box-Cox power transformation method. Results: The lowest TSH value was detected at 8-12 weeks in early pregnancy, and the median value of TSH in the T1 b subgroup was significantly lower than the T1 a subgroup (P < 0.05). TSH levels showed a gradual trend of increase along with the pregnancy and increased significantly in the T2 a, T2 b, and T3 b subgroups compared to the preceding subgroups (P < 0.05). Compared to the diagnostic criteria recommended by American Thyroid Association (ATA), the prevalence of thyroid dysfunction was significantly different from the established trimester- and subgroup-specific RIs throughout the pregnancy (P < 0.001). Conclusions: We conclude that establishing gestation- and laboratory-specific RIs, especially for TSH, is essential for diagnosing thyroid disorders in pregnancy, and the recommended universal cut-off values, which may contribute to the risk of a misdiagnosis or a missed diagnosis, should be taken with caution in the clinical setting. However, regarding the fluctuation of thyroid function tests throughout pregnancy, trimester-specific RIs are insufficient, and implementing split phases is required.

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Figures

Fig. 1 Flow chart of included/excluded pregnant women
Fig. 1 Flow chart of included/excluded pregnant womenCC BY · PubMed Central
Fig. 2 Scatter plot of gestational age versus TSH concentration with a LOESS smoothing line. The first half of the trimesters are represented with round markers and the second half with square markers. Loess nonparametric trend curve is fitted to scatter plots to reveal the trend of TSH levels throughout pregnancy
Fig. 2 Scatter plot of gestational age versus TSH concentration with a LOESS smoothing line. The first half of the trimesters are represented with round markers and the second half with square markers. Loess nonparametric trend curve is fitted to scatter plots to reveal the trend of TSH levels throughout pregnancyCC BY · PubMed Central
Fig. 3 Gestation-specific scatter plots of TSH levels for the three trimesters, including six subgroups. A First trimester; B Second trimester; C Third trimester. The first half of the trimesters are represented with round markers and the second half with square markers. Loess nonparametric trend curves (solid lines for the early trimester and dashed lines for the late trimester) are fitted to scatter plots to reveal the trend of TSH levels throughout the six subgroups
Fig. 3 Gestation-specific scatter plots of TSH levels for the three trimesters, including six subgroups. A First trimester; B Second trimester; C Third trimester. The first half of the trimesters are represented with round markers and the second half with square markers. Loess nonparametric trend curves (solid lines for the early trimester and dashed lines for the late trimester) are fitted to scatter plots to reveal the trend of TSH levels throughout the six subgroupsCC BY · PubMed Central
Fig. 4 Comparison between ATA and trimester-specific reference intervals. A First trimester; B Second trimester; C Third trimester. The figure illustrates the gaps between estimated and fixed cut-off values. For all graphs, the solid red lines are the upper and lower reference limits suggested by the ATA 2011. The dotted black lines are the upper and the lower reference limits derived from 1777 healthy pregnant women in our laboratory for each trimester
Fig. 4 Comparison between ATA and trimester-specific reference intervals. A First trimester; B Second trimester; C Third trimester. The figure illustrates the gaps between estimated and fixed cut-off values. For all graphs, the solid red lines are the upper and lower reference limits suggested by the ATA 2011. The dotted black lines are the upper and the lower reference limits derived from 1777 healthy pregnant women in our laboratory for each trimesterCC BY · PubMed Central
Fig. 5 Comparison between ATA and subgroup-specific reference intervals. A T1a subgroup; B T1b subgroup; C T2a subgroup; D T2b subgroup; E T3a subgroup; F T3b subgroup. The figure illustrates the gaps between estimated and fixed cut-off values. For all graphs, the solid red lines are the upper and lower reference limits suggested by the 2011 ATA. The dotted black lines are the upper and the lower reference limits derived from 1777 healthy pregnant women in our laboratory for each subgroup. For the subgroups T1a and T1b, the solid blue line corresponds to the upper reference limit proposed by the 2017 ATA (URL of 5.1 mIU/L, obtained by subtracting 0.5 mIU/L from the non-pregnant upper TSH level for T1a and 4.0 mIU/L for T1b subgroup)
Fig. 5 Comparison between ATA and subgroup-specific reference intervals. A T1a subgroup; B T1b subgroup; C T2a subgroup; D T2b subgroup; E T3a subgroup; F T3b subgroup. The figure illustrates the gaps between estimated and fixed cut-off values. For all graphs, the solid red lines are the upper and lower reference limits suggested by the 2011 ATA. The dotted black lines are the upper and the lower reference limits derived from 1777 healthy pregnant women in our laboratory for each subgroup. For the subgroups T1a and T1b, the solid blue line corresponds to the upper reference limit proposed by the 2017 ATA (URL of 5.1 mIU/L, obtained by subtracting 0.5 mIU/L from the non-pregnant upper TSH level for T1a and 4.0 mIU/L for T1b subgroup)CC BY · PubMed Central

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Citations

Cites

Show all 8 references

Research works printed but not linked: 34

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Metadata

Authors
Turkal, R., Turan, C. A., Elbasan, O., Aytan, S., Çakmak, B., Gözaydınoğlu, B., Takır, D. C., Ünlü, O., Bahramzada, G., Tekin, A. F., Çevlik, T., Büyükbayrak, E. E., Şirikçi, Ö., Gözü, H., & Haklar, G.
Venue
BMC Pregnancy and Childbirth
Publisher
Springer Science and Business Media LLC
Published
2022-03-31
Volume
22
Issue
1
ISSN
1471-2393
DOI
10.1186/s12884-022-04608-z
PMC
PMC8973886
Cited by
23
References
8
Language
en
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