Analysis of detection results of thyroid function-related indexes in pregnant women and establishment of the reference interval

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1 EXPERIMENTAL AND THERAPEUTIC MEDICINE Anlysis of detection results of thyroid function-relted indexes in pregnnt women nd estblishment of the reference intervl QI ZHOU 1*, YANLI ZHANG 1*, JIANHUA ZHOU 2, XIANGRONG YANG 1, YUQIANG HUANG 1, HUAFENG LI 1 nd CHUNLING MA 3 1 Clinicl Lbortory Center, Women nd Children's Helth Cre Hospitl of Linyi; 2 Deprtment of Neontology, Women nd Children's Helth Cre Hospitl of Linyi, Linyi, Shndong ; 3 Clinicl Lbortory Deprtment, Shndong Medicl College, Linyi, Shndong , P.R. Chin Received My 16, 2018; Accepted November 15, 2018 DOI: /etm Abstrct. Detection results of free thyroxine (FT4), thyroid stimulting hormone (TSH) nd thyroid peroxidse ntibody (TPOAb) in pregnnt women in Linyi region were investigted. A totl of 22,235 helthy pregnnt women dmitted to Women nd Children's Helth Cre Hospitl of Linyi from October 2016 to October 2017 were selected nd divided into the first-trimester, second-trimester nd third-trimester pregnncy groups. Non-pregnnt women in the sme period were selected s the control group. Roche E601 electrochemiluminescence pprtus ws pplied to detect FT4, TSH nd TPOAb, nd sttisticl nlysis ws then crried out for the detected dt. The positive rte in the third trimester of pregnncy ws obviously higher thn those in the first nd second trimesters of pregnncy (P<0.05). With the prolongtion of pregnncy, the reference intervl of FT4 ws grdully decresed, mong which the intervls in the second nd third trimesters of pregnncy were significntly lower thn those in the non-pregnncy (P<0.05). With the prolongtion of pregnncy, the intervl in the first trimester of pregnncy ws mrkedly smller thn tht in the non-pregnncy group. With the increse of ge, the levels of FT4 nd TSH tended to be reduced, but the TSH level ws incresed to certin degree in ptients ged over 40 yers. There were differences in the FT4 nd TSH reference intervls during pregnncy in comprison mong different regions nd different detection methods. Region-specific reference intervls need to be estblished Correspondence to: Dr Chunling M, Clinicl Lbortory Deprtment, Shndong Medicl College, 1 Juci Liu Rod, Lnshn, Linyi, Shndong , P.R. Chin E-mil: ncs2pd@163.com; mchl2003@163.com * Contributed eqully Key words: free thyroxine, thyroid stimulting hormone, thyroid peroxidse ntibody, pregnncy for different trimesters of pregnncy nd different detection methods, which is conducive to ccurte clinicl judgment of thyroid function during pregnncy. TPOAb monitoring needs to be strengthened in the third trimester of pregnncy, nd ttention should be pid to the chnges in thyroid function in pregnnt women ged over 40 yers. Introduction During pregnncy, chnges in the levels of hormones such s estrogen nd humn chorionic gondotropin (HCG) nd the incresed excretion of iodine in the kidney result in chnges in thyroid hormones in pregnnt women to vrying degrees (1). Previous findings showed tht the levels of free thyroxine (FT4) nd thyroid stimulting hormone (TSH) during pregnncy re obviously different from those during non-pregnncy (2,3). The ppliction of non-pregnncy reference intervls led to flse detection rtes to different degrees. In the Guidelines for Dignosis nd Tretment of Pregnncy nd Postprtum Thyroid Diseses stipulted by the Americn Thyroid Assocition (ATA) in 2011 (4) nd the Chinese Society of Endocrinology nd Chinese Society of Perintl Medicine of the Chinese Medicl Assocition in 2012 (2), it ws proposed tht the specific reference intervl of thyroid hormones during pregnncy needs to be estblished. In recent yers, relevnt reserch hs been conducted in mny regions in Chin (5-10), but no unified stndrd hs been formed, which repetedly confirms the necessity for estblishing region- nd methodspecific reference intervls. Therefore, sttisticl nlysis ws crried out in the present study for the detection results of thyroid hormones in helthy pregnnt women in Linyi region, so s to estblish method-specific thyroid hormone reference intervl during pregnncy in this region nd provide bsis for ccurte clinicl dignosis nd tretment. Ptients nd methods Study objects. A totl of 22,235 helthy pregnnt women receiving exmintions during pregnncy from October 2016 to October 2017 in the Women nd Children's Helth Cre

2 2 ZHOU et l: THYROID FUNCTION-RELATED INDEXES IN PREGNANT WOMEN Figure 1. SPSS 19.0 softwre ws used to plot different sttisticl grphs of the positive rte of TPOAb in different trimesters of pregnncy. Sttistics revel tht the positive rte of TPOAb is incresed with the prolonged trimester of pregnncy. Positive TPOAb is detected in totl of 873 pregnnt women in the first trimester of pregnncy (7.67%), 791 pregnnt women in the second trimester of pregnncy (9.09%), nd 253 pregnnt women in the third trimester of pregnncy (11.74%). 1, First trimester of pregnncy; 2, second trimester of pregnncy; 3, third trimester of pregnncy. Figure 3. A sctter plot of the reltionship between TSH nd ge in the first trimester of pregnncy ws drwn vi SPSS 19.0 softwre, nd liner correltion nlysis ws crried out (r 2 =0.001). In this plot, the green line is liner fitting line, nd the red line represents the verge of the ge dt. Sttistics reveled tht the detection results of TSH in the first trimester of pregnncy present skewed distribution. 990 helthy non-pregnnt women during the sme period undergoing thyroid hormone detection were selected s the control group. The study ws pproved by the Ethics Committee of Women nd Children's Helth Cre Hospitl of Linyi. Ptients who prticipted in this study hd complete clinicl dt. Signed informed consents were obtined from the ptients or gurdins. Figure 2. SPSS 19.0 softwre ws used to drw sctter plot of the correltion between FT4 nd ge in the first trimester of pregnncy, nd liner correltion nlysis ws conducted (r 2 =0.004). In this plot, the green line is liner fitting line, nd the red line represents the verge of the ge dt. Sttistics revel tht the detection results of FT4 in the first trimester of pregnncy present skewed distribution. Hospitl of Linyi (Linyi, Chin) were selected, including 11,382 ptients in the first trimester of pregnncy (within 12 weeks of pregnncy), 8,698 ptients in the second trimester of pregnncy (13-27 weeks of pregnncy) nd 2,155 ptients in the third trimester of pregnncy (more thn 28 weeks of pregnncy). The study ptients were of yers of ge nd were divided to 6 groups ccording to their ge: 20 yers group, yers group, yers group, yers group, yers group nd >40 yers group. Exclusion criteri for the study were: i) ptients with fmily history nd pst history of thyroid-relted diseses, ii) ptients tking iodine-contining drugs or drugs ffecting thyroid function (except estrogens), iii) ptients with plpble goiters, or iv) ptients with utoimmune diseses. At the sme time, Detection methods. Fsting venous blood (3 ml) ws collected in the morning nd plced in yellow vcuum tube contining cogulnts. The two were inverted nd mixed 5-8 times. After stnding t room temperture for 30 min, the mixture ws centrifuged t 1,680 x g for 5 min t 25 C to seprte the serum for detection on BY-320A centrifuge (Beijing Biyng Medicl Devices Co., Ltd., Beijing, Chin). The levels of FT4, TSH nd thyroid peroxidse ntibody (TPOAb) were detected vi Roche E601 utomtic electrochemiluminescence nlyzer. All regents were provided by Roche. Sttisticl nlysis. Sttisticl Product nd Service Solutions (SPSS) 19.0 (IBM Corp., Beijing, Chin) nd Excel softwre were employed for sttisticl nlysis. Dt in ech trimester of pregnncy were expressed s medin nd 95% bilterl limiting vlues. Enumertion dt were described by frequency nd percentge. Chi-squre test ws used for the comprison between groups. P<0.05 ws considered to indicte sttisticlly significnt difference. Results Comprison of the positive rtes of TPOAb in helthy pregnnt women in different pregnncy trimesters. Sttisticl detection reveled totl of 873 pregnnt women with positive TPOAb in the first trimester of pregnncy, nd the positive rte ws

3 EXPERIMENTAL AND THERAPEUTIC MEDICINE 3 Figure 4. SPSS 19.0 softwre ws employed to drw sctter plot of the correltion between FT4 nd ge in the second trimester of pregnncy. In this plot, the red line is liner fitting line, nd the green line represents the verge of the ge dt. Sttistics show tht the detection results of FT4 in the second trimester of pregnncy present skewed distribution. Figure 6. SPSS 19.0 softwre ws employed to drw sctter plot of the correltion between FT4 nd ge in the third trimester of pregnncy. In this plot, the red line is liner fitting line, nd the green line represents the verge of the ge dt. Sttistics revel tht the detection results of FT4 in the third trimester of pregnncy present skewed distribution. Figure 5. A sctter plot of the correltion between TSH nd ge in the second trimester of pregnncy ws drwn vi SPSS 19.0 softwre. In this plot, the red line is liner fitting line, nd the green line represents the verge of the ge dt. Sttistics revel tht the detection results of TSH in the second trimester of pregnncy present skewed distribution. Figure 7. A sctter plot of the correltion between TSH nd ge in the third trimester of pregnncy ws drwn using SPSS 19.0 softwre. In this plot, the red line is liner fitting line, nd the green line represents the verge of the ge dt. Sttistics revel tht the detection results of TSH in the third trimester of pregnncy present skewed distribution. 7.67%. A totl of 791 pregnnt women with positive TPOAb in the second trimester of pregnncy were detected, with positive rte of 9.09%. Positive TPOAb ws detected in totl of 253 pregnnt women in the third trimester of pregnncy, with positive rte of 11.74%. With the prolongtion of pregnncy, the positive rte of TPOAb incresed, nd the positive rte in the third trimester ws significntly higher thn tht in the first nd second trimesters of pregnncy (P<0.05). TPOAb 34 IU/l set by Roche regent specifictions ws considered positive (Fig. 1). Anlysis of the correltion of FT4 nd TSH detection results in helthy pregnnt women ccording to ge. According to the guideline (2), fter ptients with positive TPOAb were excluded, the remining specimens included 10,509 cses in the first trimester of pregnncy, 7,907 cses in the second trimester of pregnncy, nd 1,902 cses in the third trimester of pregnncy. FT4 nd TSH detected dt were sttisticlly nlyzed (Figs. 2-7). Comprison of the levels of FT4 in different ge groups in the first, second nd third trimesters of pregnncy. The levels of FT4, TSH, nd TPOAb were detected using Roche E601 utomtic electrochemiluminescence nlyzer, nd ll regents were provided by Roche. Sttisticl methods included SPSS 19.0 nd Excel softwre, which were pplied for

4 4 ZHOU et l: THYROID FUNCTION-RELATED INDEXES IN PREGNANT WOMEN Figure 8. Comprison of the levels of FT4 in different ge groups. (A) First trimester of pregnncy, (B) second trimester of pregnncy, (C) third trimester of pregnncy. Figure 9. Comprison of the levels of TSH in different ge groups. (A) First trimester of pregnncy, (B) second trimester of pregnncy, (C) third trimester of pregnncy. sttisticl nlysis. The medin FT4 decresed grdully with increse of ge in the second nd third trimester of pregnncy (P<0.05) (Fig. 8). Comprison of the levels of TSH in different ge groups in the first, second nd third trimesters of pregnncy. The levels of TSH in different ge groups in the first, second nd third trimesters of pregnncy were compred, nd the Roche E601 utomtic electrochemiluminescence nlyzer ws used to detect the levels of FT4, TSH nd TPOAb. The medin vlue of TSH decresed in the first nd second trimester of pregnncy, but the medin of TSH in the group of >40 yers of ge ws significntly higher thn tht in the group of yers of ge (P<0.05) (Fig. 9). Reference intervls of FT4 nd TSH in helthy pregnnt women in different trimesters of pregnncy. According to the guideline (2), fter ptients with positive TPOAb, there were 10,509 cses in the first trimester of pregnncy, 7,907 cses in the second trimester of pregnncy nd 1,902 cses in the third trimester of pregnncy. Sttisticl nlysis results of FT4 nd TSH reveled tht ll the results presented skewed distribution, nd the corresponding reference intervls were represented by medin nd 95% bilterl limiting vlues. Specific dt re shown in Tble I. Tble I lso shows tht with the prolongtion of pregnncy, the FT4 level tended to be grdully decresed wheres the TSH level ws grdully incresed. FT4 levels in the second nd third trimesters of pregnncy were mrkedly lower thn tht in the non-pregnncy, nd the differences were sttisticlly significnt. The TSH level in the first trimester of pregnncy ws notbly lower thn tht in the non-pregnncy, with sttisticlly significnt difference. Comprison of the detection results of FT4 nd TSH in pregnnt women in different ge groups. The pregnnt women were divided into five groups ccording to their ge: 20-yer group, yer group, yer group, yer group, yer group nd >40-yer group. Sttistics reveled tht the medins of FT4 in the second nd third trimesters of pregnncy showed grdul decrese in trend with ge, nd those of TSH in the first nd second trimesters of pregnncy lso exhibited tendency to decline with ge in the following groups ged below 40 yers, but they were incresed gin in the >40-yer group. In the first, second nd third trimesters of pregnncy, the medins of TSH in the >40-yer group were obviously higher thn those in 36- to 40-yer group, nd the differences were sttisticlly significnt (Tble II). Comprison of the reference intervls of FT4 nd TSH with those shown in relevnt studies in Chin. The detection results of this study were compred with those in relevnt studies in Chin (6-10), which demonstrted tht the reference intervl of FT4 ws not obviously different from those in the first trimester

5 EXPERIMENTAL AND THERAPEUTIC MEDICINE 5 Tble I. Reference intervls of FT4 nd TSH in pregnnt women in different pregnncy trimesters in Linyi region. Group n FT4 (pmol/l) TSH (miu/l) First-trimester pregnncy ( ) b 1.51 ( ),b Second-trimester pregnncy ( ) 1.90 ( ) Third-trimester pregnncy ( ) 2.14 ( ) Non-pregnncy ( ) 1.94 ( ) P<0.05 vs. non-pregnncy group, nd b P<0.05 vs. third-trimester pregnncy group. Tble II. Correltion of FT4 nd TSH medins with the ge of pregnnt women. First-trimester pregnncy Second-trimester pregnncy Third-trimester pregnncy Group n FT4 (pmol/l) TSH (miu/l) n FT4 (pmol/l) TSH (miu/l) n FT4 (pmol/l) TSH (miu/l) 20 yers yers 1, yers 4, yers 2, yers >40 yers P<0.05 vs. >40-yer group. Tble III. Comprison of FT4 detection results in different regions vi different methods. First-trimester Second-trimester Third-trimester Region Instrument pregnncy pregnncy pregnncy Non-pregnncy Shenzhen Roche ( ) ( ) ( ) ( ) Urumqi Roche ( ) ( ) ( ) ( ) Jinn Roche ( ) ( ) ( ) ( ) Zibo Beckmn ( ) 9.31 ( ) 8.05 ( ) ( ) Henn Siemens ( ) 9.31 ( ) 8.16 ( ) ( ) Linyi Roche 15.6 ( ) 13.9 ( ) 11.6 ( ) 15.5 ( ) P<0.05 vs. Linyi region. of pregnncy in Jinn, in the second trimester of pregnncy in Urumqi nd Shenzhen, nd in the third trimester of pregnncy in Jinn, but significntly different from those in other groups (P<0.05). In ddition, there were no obvious differences in the reference intervl of TSH in comprison with those in the first trimester of pregnncy in Jinn nd in the second trimester of pregnncy in Urumqi, but significnt differences were found in comprison with other groups (P<0.05). Specific results re shown in Tbles III nd IV. Discussion During pregnncy, thyroid dysfunction cn led to miscrrige, thyroid crisis, pregnncy-induced hypertension, fetl distress, intruterine growth retrdtion nd series of mternl nd fetl dverse rections (1). In prticulr, mternl hypothyroidism during pregnncy cn cuse fetl developmentl disorders in neurl intelligence, thus bringing serious burdens to fmily nd the society. Thus, it is crucil to mintin mternl norml thyroid function during pregnncy. A series of compenstory chnges occur in mternl thyroid glnds due to hormone nd immunophysiologicl chnges during pregnncy, so the thyroid function indexes during pregnncy re quite different from those during non-pregnncy. Therefore, the ppliction of reference intervls of thyroid function indexes during pregnncy my led to misdignosis nd missed dignosis to certin degree (3), nd it is necessry to estblish reference intervl for specific thyroid function during pregnncy. In the guideline stipulted in Chin (2), it is recommended to pply FT4, TSH nd TPOAb s indexes of thyroid screening

6 6 ZHOU et l: THYROID FUNCTION-RELATED INDEXES IN PREGNANT WOMEN Tble IV. Comprison of TSH detection results in different regions vi different methods. First-trimester Second-trimester Third-trimester Region Instrument pregnncy pregnncy pregnncy Non-pregnncy Shenzhen Roche 1.10 ( ) 2.07 ( ) 2.62 ( ) 2.63 ( ) Urumqi Roche 1.85 ( ) 1.89 ( ) 2.57 ( ) 2.09 ( ) Jinn Roche 1.52 ( ) 2.39 ( ) 2.52 ( ) 2.68 ( ) Zibo Beckmn 1.78 ( ) 2.14 ( ) 2.40 ( ) 2.67 ( ) Henn Siemens 1.68 ( ) 2.03 ( ) 2.31 ( ) 2.35 ( ) Linyi Roche 1.51 ( ) 1.90 ( ) 2.14 ( ) 1.94 ( ) P<0.05 vs. Linyi region. during pregnncy. The guideline suggests tht the positive dignostic criteri of TPOAb is higher thn the upper limit of the reference vlue provided by the kit. Therefore, sttisticl nlyses were minly conducted for reference intervls of the two indexes, FT4 nd TSH, in this study. TPOAb is produced by the relese of thyroid peroxidse (TPO) from the follicles of thyroid glnds into the blood to stimulte the body's immune system, thereby reducing the production of thyroid hormones nd stimulting TSH secretion. Positive TPOAb often indictes the presence of thyroid dmge nd my increse the risks of miscrrige nd premture delivery. Reports worldwide hve demonstrted tht the positive rte of TPOAb during pregnncy is in the rnge of % (11-13). However, in this study, the positive rtes of TPOAb in the first, second nd third trimesters of pregnncy were 7.67, 9.09 nd 11.74%, respectively, with the overll positive rte of 8.62%, which ws slightly lower thn results in other reports. This my be relted to the detection method, the iodine sttus of the region, nd the number of the detected individuls. This study showed tht the TPOAb positive rte in the third trimester of pregnncy is considerbly higher thn tht in the first trimester of pregnncy, indicting sttisticlly significnt difference. For pregnnt women in the third trimester of pregnncy, monitoring of TPOAb should be strengthened. It ws lso found in this study tht the FT4 level in the third trimester is remrkbly lower thn tht in the first trimester pregnncy, while the TSH level in the third trimester of pregnncy ws notbly higher thn tht in the first trimester of pregnncy, suggesting tht the probbility of hypothyroidism in pregnnt women in the third trimester of pregnncy is greter, which needs prticulr ttention. The present study reveled tht with the prolongtion of pregnncy, the FT4 level exhibited grdully decresing trend while the TSH level hd grdully incresing trend, which is consistent with the reserch findings of other scholrs (6-11). The FT4 level in the third trimester of pregnncy ws significntly lower thn tht in the first trimester. The underlying cuse my be tht the incresed excretion rte of iodine in the kidney of pregnnt women in the third trimester of pregnncy nd the incresed demnd for iodine in the fetus result in reltive lck of mternl iodine (14), thus leding to the decresed production of thyroid hormones. TSH level in the first trimester of pregnncy ws obviously lower thn tht in the third trimester of pregnncy. This is minly becuse HCG peks t 8-10 weeks of pregnncy nd then continues to decline, the lph subunits of HCG nd TSH re similr, nd the negtive feedbck regultion leds to mrked decrese in the TSH level in the first trimester of pregnncy, which is then grdully incresed. In the second nd third trimesters of pregnncy, the FT4 level tended to decrese with the increse of the ge of pregnnt womn, which is similr to the results of Kuo et l (15) nd Ademuyiw et l (16). This my be relted to the hyposecretion of hormones with the increse of ge (16), but the specific reson hs yet to be determined. The chnged trend in TSH in this study is contrry to tht in the study of Ademuyiw et l (16). In this study, it ws found tht TSH exhibited tendency to decline with the increse of ge in women ged <40 yers, nd it only tended to be incresed in the >40-yer group, which might be due to the different reserch groups nd the number of included ptients. In the 40-yer group, the FT4 level ws the lowest mong ll ge groups, while the TSH level ws mrkedly higher thn tht in 35- to 40-yer group, suggesting tht the occurrence probbility of hypothyroidism is higher in the 40-yer group. Recent studies worldwide hve proposed tht region- nd method-specific reference intervls for thyroid function during pregnncy need to be estblished for self-serving popultions in vrious prentl screening centers (5,17). Comprisons of study results of relted institutions in Chin (6-10) lso verify this view. Using the sme detection method, significnt differences were found in FT4 nd TSH levels in groups in Linyi except FT4 levels in the first nd third trimesters of pregnncy nd TSH level in the first trimester of pregnncy compred with those in Jinn. Compred with those in Urumqi, significnt differences were detected in FT4 nd TSH levels in ll groups except FT4 nd TSH levels in the second trimester of pregnncy. Compred with those in Shenzhen, there were notble differences in FT4 nd TSH levels in ll the groups except FT4 level in the second trimester of pregnncy (P<0.05). Detection results were notbly different mong different detection methods regrdless of the region (P<0.05). Therefore, it is impertive to estblish region- nd method-specific thyroid hormone reference intervls during pregnncy. In summry, thyroid hormones during pregnncy vry with pregnncy, region, nd detection methods. Ech region

7 EXPERIMENTAL AND THERAPEUTIC MEDICINE 7 or medicl institution should estblish its own specific thyroid hormone reference intervls during pregnncy to provide ccurte dignostic criteri for the region or medicl institution. Thyroid hormones during pregnncy chnge with ge nd pregnncy. For pregnnt women ged over 40 yers in the third trimester of pregnncy, thyroid hormone levels need intensive monitoring. Acknowledgements Not pplicble. Funding This study ws supported by the Science nd Technology Development nd Innovtion Project in Linyi (contrct no ). Avilbility of dt nd mterils The dtsets used nd/or nlyzed during the present study re vilble from the corresponding uthor on resonble request. Authors' contributions QZ nd YZ collected the dt of ptents nd extrcted venous blood. JZ nd XY recorded nd interpreted FT4 level. YH nd HL nlyzed TSH levels. QZ, YZ nd CM were responsible for the sttisticl nlysis. All uthors red nd pproved the finl mnuscript. Ethics pprovl nd consent to prticipte The study ws pproved by the Ethics Committee of Women nd Children's Helth Cre Hospitl of Linyi (Linyi, Chin). Ptients who prticipted in this study hd complete clinicl dt. Signed informed consents were obtined from the ptients or gurdins. Ptient consent for publiction Not pplicble. Competing interests The uthors declre tht they hve no competing interests. References 1. Teng WP nd Shn ZY: Confusion nd thought of the dignosis nd tretment for thyroid diseses in pregnncy. Zhonghu Nei Ke Z Zhi 51: 1-4, 2012 (In Chinese). 2. Alexnder EK, Perce EN, Brent GA, Brown RS, Chen H, Dosiou C, Grobmn WA, Lurberg P, Lzrus JH, Mndel SJ, et l: 2017 Guidelines of the Americn Thyroid Assocition for the dignosis nd mngement of thyroid disese during pregnncy nd the postprtum. 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