Subclinical Hypothyroidism in Pregnancy: How Great Are the Real Risks and Can They Be Effectively Reduced?
The aim of the meta-analysis by authors from the Mayo Clinic was to describe the impact of subclinical hypothyroidism on the course of pregnancy and the effect of levothyroxine replacement therapy in reducing the risk of possible complications.
Risks Associated with Subclinical Hypothyroidism
Subclinical hypothyroidism (SCH) is defined by elevated thyrotropin (TSH) levels and normal thyroxine (T4) levels in serum. Using new diagnostic criteria (upper limit of TSH during the first trimester 2.5 mIU/l and for the rest of pregnancy 3.0 mIU/l), up to 15% of pregnant women in the USA suffer from SCH.
Unlike overt hypothyroidism, the consequences of SCH are not precisely described. Several studies link SCH with higher risks of complications during and after pregnancy, such as miscarriages, preterm births, gestational diabetes mellitus, gestational hypertension, preeclampsia, placental abruption, preterm rupture of membranes, intrauterine growth restriction, low birth weight, small size for gestational age, low Apgar scores, and neonatal deaths. High TSH levels have been associated in some analyses with an increased risk of neurocognitive impairment in offspring. Other studies, however, have not observed any risks associated with SCH.
Therefore, it is unclear what impact levothyroxine replacement therapy has on improving pregnancy outcomes. A team of doctors from the Mayo Clinic in the USA conducted a systematic review and meta-analysis of available clinical studies in 2016.
Meta-Analysis Results
A total of 18 cohort studies with low to moderate risk of bias and a total of 3995 pregnant women diagnosed with SCH were included in the analysis. Compared to pregnant women with normal thyroid function, an association was observed between the occurrence of SCH during pregnancy and higher risks of miscarriage (relative risk [RR] 2.01; 95% confidence interval [CI] 1.66–2.44; I2 = 0 %), placental abruption (RR 2.14; CI 1.23–3.70; I2 = 0 %), preterm rupture of membranes (RR 1.43; CI 1.04–1.95; I2 = 9 %), and neonatal death (RR 2.58; CI 1.41–4.73; I2 = 0 %). There was no observed correlation with other risks.
An observational study, which was not included in the analysis due to high risk of bias, examined thyroid function in pregnant women in the first trimester. Women diagnosed with SCH were recommended to take levothyroxine, but only 14% started this therapy. The study described an increased risk of miscarriage in women with SCH compared to pregnant women with normal thyroid function (RR 1.75; CI 1.12–2.73). Due to the small number of patients with SCH on replacement therapy (n = 28) and high risk of selection bias, statistically significant risks of miscarriage, preterm birth, gestational hypertension, low birth weight, and low Apgar scores were not demonstrated when compared to pregnant women with SCH without replacement therapy (n = 168).
Effect of Levothyroxine Therapy According to Recent Meta-Analysis
Recently, Chinese authors from Sichuan University conducted an updated systematic review and meta-analysis of data from 9 databases up to February 2022. They specifically addressed the impact of levothyroxine replacement therapy on clinical outcomes of women with SCH. The analysis included 9 randomized controlled trials (RCTs) and 13 cohort studies with a total of 11,273 pregnant women with SCH. In the overall population, no statistically significant differences were found in the occurrence of miscarriages, gestational hypertension, gestational diabetes, or small size for gestational age (moderate quality evidence).
In sub-analyses of the population of women for whom results of anti-thyroid peroxidase antibodies (anti-TPO) were available, levothyroxine therapy was associated with a reduced risk of preterm birth, miscarriage, gestational hypertension, and gestational diabetes. However, the quality of evidence was low or very low due to the methodology of the included studies.
In the main meta-analysis including only RCTs, a trend towards reduced risk of preterm birth, miscarriage, placental abruption, and low birth weight was observed. However, the included studies did not have enough power for statistically significant conclusions.
Summary and Conclusion
According to the systematic review of 18 studies with low to moderate risk of bias and a total of 3995 pregnant women with SCH, these women have an increased risk of miscarriage, placental abruption, preterm rupture of membranes, and neonatal death compared to the euthyroid population.
The 2022 meta-analysis of 9 RCTs did not demonstrate a statistically significant impact of replacement therapy on clinical outcomes of women with SCH, but a positive trend was observed. The meta-analysis was conducted on a relatively small sample of patients, so methodologically robust randomized trials with large samples of participants could provide definitive evidence of the benefits of including replacement therapy in the future.
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Sources:
1. Maraka S., Ospina N. M., O'Keeffe D. T. et al. Subclinical hypothyroidism in pregnancy: a systematic review and meta-analysis. Thyroid 2016; 26 (4): 580–590, doi: 10.1089/thy.2015.0418.
2. Jiao X. F., Zhang M., Chen 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. Front Endocrinol (Lausanne) 2022 Aug 5; 13: 964084, doi: 10.3389/fendo.2022.964084.
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