A meta-analysis of the effects of levothyroxine dose adjustment on maternal and infant outcomes in pregnant women with hypothyroidism

doi:10.3969/j.issn.1674-8115.2023.07.013

Abstract

Abstract:

Objective ·To evaluate the effects of levothyroxine (L-T4) dose adjustment according to the level of thyroid stimulating hormone (TSH) on maternal and infant outcomes in the pregnant women with hypothyroidism by meta-analysis. Methods ·China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), Wanfang Data Knowledge Service Platform, PubMed, Cochrane Library and Embase were retrieved to collect all the controlled studies on the treatment of pregnant women with hypothyroidism by adjusting the dose of L-T4 according to TSH level from the establishment of the databases to April 9, 2022. The references were also traced. Literature screening, data extraction, and quality evaluation were performed independently by two researchers. Cochrane evaluation was used to evaluate the quality of the included literature. Outcome indicators included gestational hypertension, gestational diabetes, postpartum hemorrhage, delivery mode, preterm birth, fetal death, neonatal asphyxia, and low birth weight infants. RevMan 5.3 was used for meta-analysis. Result ·A total of 1 268 articles were retrieved from 6 databases, and 8 were included in the study, including 4 Chinese articles and 4 English articles. The overall risk of study bias was at a moderate level. Compared with the control group, the OR of gestational diabetes risk was 0.61 (95%CI 0.44?0.86, P=0.004) and the OR of fetal death risk was 0.38 (95%CI 0.18?0.81, P=0.010) in the experimental group with L-T4 dose adjusted according to the TSH level of the pregnant women with hypothyroidism, which were both statistically significant. However, the treatment method of adjusting L-T4 dose did not affect the risks of vaginal delivery [OR=1.82 (95%CI 0.75?4.40, P=0.180)], gestational hypertension [OR=0.77 (95%CI 0.53?1.12, P=0.170)], postpartum hemorrhage [OR=1.20 (95%CI 0.50?2.92, P=0.680)], preterm birth [OR=0.72 (95%CI 0.48?1.06, P=0.100)], low birth weight infants [OR=1.00 (95%CI 0.65?1.54, P=0.999)], or neonatal asphyxia [OR=0.50 (95%CI 0.20?1.27, P=0.150)] significantly. Conclusion ·Adjusting the L-T4 therapeutic dose according to the TSH level may help reduce the risks of gestational diabetes and fetal death in the pregnant women with hypothyroidism.

Key words: hypothyroidism, pregnant woman, levothyroxine (L-T4), dose adjustment, maternal and infant outcome, meta-analysis

CLC Number:

R714.7

CHEN Hui, ZHU Weiyi, YAO Yijin. A meta-analysis of the effects of levothyroxine dose adjustment on maternal and infant outcomes in pregnant women with hypothyroidism[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(7): 906-915.

Figures/Tables 11

TrendMD

References 30

1	DONG A C, STAGNARO-GREEN A. Differences in diagnostic criteria mask the true prevalence of thyroid disease in pregnancy: a systematic review and meta-analysis[J]. Thyroid, 2019, 29(2): 278-289.
2	ABALOVICH M, GUTIERREZ S, ALCARAZ G, et al. Overt and subclinical hypothyroidism complicating pregnancy[J]. Thyroid, 2002, 12(1): 63-68.
3	SULLIVAN S A. Hypothyroidism in pregnancy[J]. Clin Obstet Gynecol, 2019, 62(2): 308-319.
4	The Consortium on Thyroid and Pregnancy-Study Group on Preterm Birth. Association of thyroid function test abnormalities and thyroid autoimmunity with preterm birth: a systematic review and meta-analysis[J]. JAMA, 2019, 322(7): 632-641.
5	MARAKA S, OSPINA N M S, O′KEEFFE D T, et al. Subclinical hypothyroidism in pregnancy: a systematic review and meta-analysis[J]. Thyroid, 2016, 26(4): 580-590.
6	SULLIVAN S D, DOWNS E, POPOVENIUC G, et al. Randomized trial comparing two algorithms for levothyroxine dose adjustment in pregnant women with primary hypothyroidism[J]. J Clin Endocrinol Metab, 2017, 102(9): 3499-3507.
7	TOLOZA F J K, ABEDZADEH-ANARAKI S, MARAKA S. Subclinical hypothyroidism in pregnancy[J]. Curr Opin Endocrinol Diabetes Obes, 2019, 26(5): 225-231.
8	高金保. 观察妊娠期亚临床甲减以及甲状腺激素干预治疗对妊娠结局的影响[J]. 云南医药, 2021, 42(4): 345-347.
	GAO J B. Observation of the effect of subclinical hypothyroidism during pregnancy and thyroid hormone intervention on pregnancy outcome[J]. Medicine and Pharmacy of Yunnan, 2021, 42(4):345-347.
9	叶晓梅, 陈友英. 左旋甲状腺素片治疗妊娠合并甲状腺功能减退28例剂量调整[J]. 中国妇幼健康研究, 2016, 27(S1): 425.
	YE X M,CHEN Y Y. Dose adjustment of levothyroxine tablets for 28 cases of pregnancy complicated with hypothyroidism[J]. Chinese Journal of Woman and Child Health Research, 2016, 27(S1): 425.
10	马玉红. 左旋甲状腺素钠片的不同剂量对妊娠期甲减患者的治疗效果分析[J]. 医学理论与实践, 2020, 33(18): 3060-3062.
	MA Y H. Analysis of therapeutic effect of different doses of levothyroxine sodium tablets on pregnant women with hypothyroidism [J]. The Journal of Medical Theory and Practice, 2020, 33(18): 3060-3062.
11	柳丽君. 左旋甲状腺素片治疗妊娠合并甲减患者剂量调整分析[J]. 海峡药学, 2021, 33(7): 181-182
	LIU L J. Dose adjustment analysis of levothyroxine tablets for pregnant women with hypothyroidism[J]. Strait Pharmaceutical Journal, 2021, 33(7): 181-182.
12	CASEY B M, THOM E A, PEACEMAN A M, et al. Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy[J]. N Engl J Med, 2017, 376(9): 815-825.
13	BLUMENTHAL N J, EASTMAN C J. Beneficial effects on pregnancy outcomes of thyroid hormone replacement for subclinical hypothyroidism[J]. J Thyroid Res, 2017, 2017: 4601365.
14	WANG S, TENG W P, LI J X, et al. Effects of maternal subclinical hypothyroidism on obstetrical outcomes during early pregnancy[J]. J Endocrinol Invest, 2012, 35(3): 322-325.
15	JU R, LIN L, LONG Y, et al. Clinical efficacy of therapeutic intervention for subclinical hypothyroidism during pregnancy[J]. Genet Mol Res, 2016, 15(4). DOI: 10.4238/gmr15049019.
16	李春莉, 黄卉, 李秋红. 妊娠早期亚临床甲状腺功能减退与妊娠糖尿病的相关性研究[J]. 中华内分泌代谢杂志, 2014, 30(9): 747-748.
	LI C L, HUANG H, LI Q H. Relationship of subclinical hypothyroidism with gestational diabetes mellitus during early pregnancy[J]. Chinese Journal of Endocrinology and Metabolism, 2014, 30(9): 747-748.
17	DERAKHSHAN A, KOREVAAR T I M, TAYLOR P N, et al. The association of maternal thyroid autoimmunity during pregnancy with child IQ[J]. J Clin Endocrinol Metab, 2018, 103(10): 3729-3736.
18	刘娟弟, 王瑞, 何菊仙. 甲状腺功能减退与孕早期自发性流产的相关性分析[J]. 医学临床研究, 2022, 39(2): 232-235
	LIU J D, WANG R, HE J X. Relationship between hypothyroidism and spontaneous abortion in early pregnancy[J]. Journal of Clinical Research, 2022, 39(2): 232-235.
19	ALEXANDER E K, PEARCE E N, BRENT G A, et al. 2017 guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum[J]. Thyroid, 2017, 27(3): 315-389.
20	DING Z, LIU Y D, MARAKA S, et al. Pregnancy and neonatal outcomes with levothyroxine treatment in women with subclinical hypothyroidism based on new diagnostic criteria: a systematic review and meta-analysis[J]. Front Endocrinol (Lausanne), 2021, 12: 797423.
21	JIAO X F, ZHANG M, CHEN J J, et al. The impact of levothyroxine therapy on the pregnancy, neonatal and childhood outcomes of subclinical hypothyroidism during pregnancy: an updated systematic review, meta-analysis and trial sequential analysis[J]. Front Endocrinol (Lausanne), 2022, 13: 964084.
22	MAGRI F, CHIOVATO L, CROCE L, et al. Thyroid hormone therapy for subclinical hypothyroidism[J]. Endocrine, 2019, 66(1): 27-34.
23	PEARCE E N. Management of hypothyroidism and hypothyroxinemia during pregnancy[J]. Endocr Pract, 2022, 28(7): 711-718.
24	单忠艳, 滕卫平. 《妊娠和产后甲状腺疾病诊治指南》(第2版)要点解读[J]. 中华内分泌代谢杂志, 2019, 35(8): 632-635.
	SHAN Z Y, TENG W P. Guideline on diagnosis and management of thyroid diseases during pregnancy and postpartum (2nd edition): an essential introduction[J]. Chinese Journal of Endocrinology and Metabolism, 2019, 35(8): 632-635.
25	《孕产期甲状腺疾病防治管理指南》编撰委员会, 中华医学会内分泌学分会, 中华预防医学会妇女保健分会. 孕产期甲状腺疾病防治管理指南[J]. 中华内分泌代谢杂志, 2022, 38(7): 539-551.
	Writing Committee for Guidelines for Prevention and Management of Thyroid Diseases During Pregnancy and Perinatal Period, Chinese Society of Endocrinology, Chinese Medical Association, Women′s Health Care Branch of Chinese Preventive Medicine Association. Guidelines for prevention and management of thyroid diseases during pregnancy and perinatal period[J]. Chinese Journal of Endocrinology and Metabolism, 2022, 38(7): 539-551.
26	HUBALEWSKA-DYDEJCZYK A, TROFIMIUK-MÜLDNER M, RUCHALA M, et al. Thyroid diseases in pregnancy: guidelines of the Polish Society of Endocrinology[J]. Endokrynol Pol, 2021, 72(5): 425-488.
27	王文娟. 左甲状腺素钠片对妊娠期甲减患者甲状腺功能、不良反应及妊娠结局的改善效果[J]. 实用妇科内分泌电子杂志, 2022, 9(12): 27-30.
	WANG W J. Effects of levothyroxine sodium tablets on thyroid function, adverse reactions and pregnancy outcomes in patients with hypothyroidism during pregnancy[J]. Electronic Journal of Practical Gynecological Endocrinology, 2022, 9(12): 27-30.
28	HAN Y, WANG J, WANG X Y, et al. Relationship between subclinical hypothyroidism in pregnancy and hypertensive disorder of pregnancy: a systematic review and meta-analysis[J]. Front Endocrinol (Lausanne), 2022, 13: 823710.
29	宋茜茜, 李志红, 郭淑芹, 等. 妊娠糖尿病伴亚临床甲减对孕妇骨密度及骨钙素、25-羟基维生素D的影响[J]. 中国计划生育学杂志, 2020, 28(1): 56-59
	SONG Q Q, LI Z H, GUO S Q, et al. Effect of disease of pregnant women with gestational diabetes mellitus and subclinical hypothyroidism on their bone mineral density, and levels of osteocalcin and 25-hydroxyvitamin D[J]. Chinese Journal of Family Planning, 2020, 28(1): 56-59.
30	VELASCO I, VILA L, GOYA M, et al. Executive summary of the SEEN (Sociedad Española de Endocrinología y Nutrición [Spanish Society of Endocrinology and Nutrition])-SEGO (Sociedad Española deGinecología y Obstetricia [Spanish Society of Gynaecology and Obstetrics]) consensus document on the management of thyroid dysfunction during pregnancy[J]. Endocrinol Diabetes Nutr (Engl Ed), 2023, 70(Suppl 1): 38-50.

First author	Year of publica-tion	Nation	Number of cases/n		Age/year		Intervention		Primary outcome index
First author	Year of publica-tion	Nation	Exp	Con	Exp	Con	Exp	Con	Primary outcome index
GAO^[8]	2021	China	46	34	25.3±3.4	24.8±3.1	Guidance on routine maternal care was given. The initial dose of L-T4 was 50 μg/d. TSH level was re-examined 2 weeks later and the dose was adjusted	Guidance on routine maternal care was given. The iodized salt was increased and the fat was reduced in the diet	GH, PH, GDM, PD
YE^[9]	2016	China	28	28	22-34	22-34	The fat was reduced, and the iodized salt and the protein were increased in the diet. Routine medication and nursing interventions were given. TSH was checked every 4‒6 weeks and the L-T4 dose was adjusted	The fat was reduced, and the iodized salt and the protein were increased in the diet. Routine medication and nursing interventions were given	GDM, GH, DM, LBW, FD, NA
MA^[10]	2020	China	42	42	28.74±4.08	28.25±4.15	The fat was reduced, and the iodized salt and the protein were increased in the diet. TSH level was checked once a month and the L-T4 dose was adjusted	The fat was reduced, and the iodized salt and the protein were increased in the diet. The dose of L-T4 was 50 μg/d	GH, GDM, FD, PD, NA, LBW, DM, abortion
LIU^[11]	2021	China	49	49	26.9±4.6	26.8±4.7	The fat was reduced, and the iodized salt and the protein were increased in the diet. TSH level was checked termly and the L-T4 dose was adjusted	The fat was reduced, and the iodized salt and the protein were increased in the diet. The dose of L-T4 was 25 μg/d	DM, FD, abortion, PD, NA, LBW
CASEY^[12]	2017	America	339	338	27.7±5.7	27.3±5.7	The initial dose of L-T4 was 100 μg/d. TSH level was checked once a month and the L-T4 dose was adjusted. TSH level was controlled in the range of 0.1‒2.5 mIU/L	A placebo of 100 μg was given daily with a dummy adjustment	GDM, GH, LBW, PD, FD
BLUMENTHAL^[13]	2017	Australia	92	933	33.47±1.41	35.00±5.20	The iodized salt was increased in the diet. The dose of L-T4 was 50 μg/d when TSH>2.5 mIU/L. TSH was checked every 4 weeks and the L-T4 dose was adjusted	The iodine was increased in diet and L-T4 was not given	DM, GH, GDM, PD, FD
WANG^[14]	2012	China	28	168	Not mentioned	28.14±0.27	The initial dose of L-T4 depended on the pregnant woman′s TSH level. TSH 2.5‒5 mIU/L: L-T4 50 μg/d; TSH >5‒8 mIU/L: L-T4 75 μg/d; TSH>8 mIU/L: L-T4 100 μg/d. TSH level was checked every 4 weeks and the L-T4 dose was adjusted	L-T4 was not given	GH, PD, LBW, PH, abortion, NA
JU^[15]	2016	China	184	273	29.31±3.36	28.88±3.53	The initial LT-4 dose was determined based on TSH level. Dose of LT-4 was adjusted according to the treatment objective of TSH	L-T4 was not given	GDM, GH, PH, PD, LBW

First author	Year of publica-tion	Nation	Number of cases/n		Age/year		Intervention		Primary outcome index
First author	Year of publica-tion	Nation	Exp	Con	Exp	Con	Exp	Con	Primary outcome index
GAO^[8]	2021	China	46	34	25.3±3.4	24.8±3.1	Guidance on routine maternal care was given. The initial dose of L-T4 was 50 μg/d. TSH level was re-examined 2 weeks later and the dose was adjusted	Guidance on routine maternal care was given. The iodized salt was increased and the fat was reduced in the diet	GH, PH, GDM, PD
YE^[9]	2016	China	28	28	22-34	22-34	The fat was reduced, and the iodized salt and the protein were increased in the diet. Routine medication and nursing interventions were given. TSH was checked every 4‒6 weeks and the L-T4 dose was adjusted	The fat was reduced, and the iodized salt and the protein were increased in the diet. Routine medication and nursing interventions were given	GDM, GH, DM, LBW, FD, NA
MA^[10]	2020	China	42	42	28.74±4.08	28.25±4.15	The fat was reduced, and the iodized salt and the protein were increased in the diet. TSH level was checked once a month and the L-T4 dose was adjusted	The fat was reduced, and the iodized salt and the protein were increased in the diet. The dose of L-T4 was 50 μg/d	GH, GDM, FD, PD, NA, LBW, DM, abortion
LIU^[11]	2021	China	49	49	26.9±4.6	26.8±4.7	The fat was reduced, and the iodized salt and the protein were increased in the diet. TSH level was checked termly and the L-T4 dose was adjusted	The fat was reduced, and the iodized salt and the protein were increased in the diet. The dose of L-T4 was 25 μg/d	DM, FD, abortion, PD, NA, LBW
CASEY^[12]	2017	America	339	338	27.7±5.7	27.3±5.7	The initial dose of L-T4 was 100 μg/d. TSH level was checked once a month and the L-T4 dose was adjusted. TSH level was controlled in the range of 0.1‒2.5 mIU/L	A placebo of 100 μg was given daily with a dummy adjustment	GDM, GH, LBW, PD, FD
BLUMENTHAL^[13]	2017	Australia	92	933	33.47±1.41	35.00±5.20	The iodized salt was increased in the diet. The dose of L-T4 was 50 μg/d when TSH>2.5 mIU/L. TSH was checked every 4 weeks and the L-T4 dose was adjusted	The iodine was increased in diet and L-T4 was not given	DM, GH, GDM, PD, FD
WANG^[14]	2012	China	28	168	Not mentioned	28.14±0.27	The initial dose of L-T4 depended on the pregnant woman′s TSH level. TSH 2.5‒5 mIU/L: L-T4 50 μg/d; TSH >5‒8 mIU/L: L-T4 75 μg/d; TSH>8 mIU/L: L-T4 100 μg/d. TSH level was checked every 4 weeks and the L-T4 dose was adjusted	L-T4 was not given	GH, PD, LBW, PH, abortion, NA
JU^[15]	2016	China	184	273	29.31±3.36	28.88±3.53	The initial LT-4 dose was determined based on TSH level. Dose of LT-4 was adjusted according to the treatment objective of TSH	L-T4 was not given	GDM, GH, PH, PD, LBW

[1]	MA Zhuoran, YUAN Ancai, JIANG Huiru, CHEN Xiaoyu, ZHANG Wei, PU Jun. Meta analysis of correlation between lipid accumulation product and hypertension in Chinese adults [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(4): 466-473.
[2]	YANG Ling, HOU Lili, ZHAO Yan, CHEN Weihong, ZHANG Jinfeng, MAO Yan. A meta-analysis of prevalence of mouth opening restriction in patients with oral cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(1): 61-69.
[3]	FANG Fang, TAI Rui, YU Qian, ZHANG Yaqing. Effect of prehabilitation on outcomes in patients undergoing elective gastrointestinal surgery: a systematic review [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(1): 70-78.
[4]	CHEN Weihong, HOU Lili, YANG Ling, MAO Yan, ZHANG Jinfeng. Efficacy of preventive intervention of cryotherapy on radiation-induced oral mucositis in head and neck cancer: a meta-analysis [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(5): 635-645.
[5]	Yingchao TAN, Junyue YANG, Lina WANG. Association between interleukin-1B-511C/T gene polymorphism and coronary atherosclerotic heart disease: a meta-analysis [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2022, 42(2): 197-204.
[6]	Dewei QIAN, Ren ZHOU, Lichun GUAN, Hang ZHANG, Min YU. Meta-analysis of impacts of inhaled nitric oxide on postoperative renal injury and hemorrhage [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2022, 42(1): 95-100.
[7]	Yi WANG, Cheng CHENG, Hong-yan SHEN, Hong-yan GAO, Yue-ning DAI, Zheng-hui YI. Meta-analysis of efficacy of transcranial magnetic stimulation for the treatment of cognitive function and behavioral and psychological symptoms of dementia in patients with Alzheimer′s disease [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(7): 931-941.
[8]	Jie LIU, Xin-min XIE, Xue-mei ZHI, Jing-yi LU. Meta-analysis of the relationship between sleep duration and the risk of diabetic retinopathy [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(11): 1502-1508.
[9]	Zhi-ling CHEN, Chen LUO, Kang-jia ZHAO, Ling SHEN, San-lian HU. Application of two kinds of analgesia after colorectal cancer surgery: a meta-analysis [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(10): 1344-1350.
[10]	PAN Sheng-ke, LI Hui, WEI Yan-yan, YAO Pei-fen, LI Hua-fang. Placebo effect in primary insomnia: a meta-analysis [J]. , 2020, 40(4): 505-.
[11]	HUANG Yan, ZHANG Xian-gao, LIN Heng, CHENG Shu-ying. Meta-analysis of effect and safety of repetitive transcranial magnetic stimulation on patients with schizophrenia [J]. , 2020, 40(1): 81-.
[12]	QIN Kai-li1, LIU An-ming2, YUAN Chong-gang3, SHI Rong1, YAO Qian1, CAI Chen4, ZHOU Yi-jun1, TIAN Ying1, 5, ZHANG Yan1, GAO Yu1. Exposure status of multiple environmental pollutants during pregnancy: based on biomonitoring data Laizhou Wan Birth Cohort in Shandong [J]. , 2019, 39(4): 421-.
[13]	WANG Ye-wei, CHEN Yan, FANG Xin-yu, ZHANG Yi, CAI Jun, SONG Li-sheng, ZHANG Chen. Association of serum olanzapine concentration and cytochrome P450 1A2 gene polymorphisms: a meta-analysis [J]. , 2019, 39(10): 1167-.
[14]	XU Fei, TANG Ling-lin, YUAN Hong, SONG Shao-li, HUANG Gang. Analysis of liver function, serum lipid and blood routine in patients with differentiated thyroid cancer before radioactive iodine treatment [J]. , 2018, 38(6): 632-.
[15]	MAO Yi-ming, WEI Chang-jiang, WU Chang-jiang, QIN Yuan, LU Jia-hao, LU Wen-qiang. Comparison of efficacy of video-assisted thoracic surgery and conventional lung volume reduction surgery for the treatment of patients with severe chronic obstructive pulmonary disease: a meta-analysis [J]. , 2017, 37(7): 997-.