Background: The impact of subclinical hypothyroidism (SCH) and of levothyroxine replacement in pregnant women with SCH is unclear. The aims of this study were to assess (i) the impact of SCH during pregnancy on maternal and neonatal outcomes, and (ii) the effect of levothyroxine replacement therapy in these patients.
Methods: Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, the Cochrane Controlled Trials Register, Ovid EMBASE, Web of Science, and Scopus were searched from inception to January 2015. Randomized trials and cohort studies of pregnant women with SCH that examined adverse pregnancy and neonatal outcomes were included. Reviewers extracted data and assessed methodological quality in duplicate. Eighteen cohort studies at low-to-moderate risk of bias were included. Compared with euthyroid pregnant women, pregnant women with SCH were at higher risk for pregnancy loss (relative risk [RR] 2.01 [confidence interval (CI) 1.66-2.44]), placental abruption (RR 2.14 [CI 1.23-3.70]), premature rupture of membranes (RR 1.43 [CI 1.04-1.95]), and neonatal death (RR 2.58 [CI 1.41-4.73]). One study at high risk of bias compared pregnant women with SCH who received levothyroxine to those who did not and found no significant decrease in the rate of pregnancy loss, preterm delivery, gestational hypertension, low birth weight, or low Apgar score.
Conclusions: SCH during pregnancy is associated with multiple adverse maternal and neonatal outcomes. The value of levothyroxine therapy in preventing these adverse outcomes remains uncertain.
Hypothyroidism is a condition that is caused by an underactive thyroid gland. It may happen during pregnancy. Many symptoms of the condition are similar to pregnancy symptoms. For example, they can both cause fatigue, weight gain, and changes in menstruation. Having low thyroid hormone levels can also cause problems with becoming pregnant. It can also be a cause of miscarriage.
During the first few months of pregnancy, the baby relies on the mother for thyroid hormones. These hormones are vital for normal brain development and growth of the baby. Hypothyroidism in the mother can have long-lasting effects on the baby.
You will have blood tests that measure thyroid hormone (thyroxine, or T4) and serum TSH (thyroid-stimulating hormone) levels. TSH levels that are above normal and T4 levels that are below normal may mean you have hypothyroidism.
Routine screening for hypothyroidism during pregnancy is not advised. A pregnant woman with symptoms of hypothyroidism, a history of the condition, or with other endocrine system conditions should be tested.
Thyroid hormone replacement is used to treat the mother. The amount of thyroid hormone given is based on the mother's levels of thyroid hormones as well as her symptoms. Thyroid hormone levels may change during pregnancy. The hormone replacement dose will likely change over time. Thyroid hormone levels need to be checked every 4 weeks in the first half of pregnancy. The levels may be checked less often during the second half of pregnancy as long as the dose does not change. The treatment is safe and vital to both mother and baby. Thyroid hormones should not be taken at the same time as prenatal vitamins. This is because the minerals in the vitamins may stop the absorption of the thyroid hormone. All newborns are screened at birth to check thyroid hormone levels.
Levothyroxine replacement therapy may decrease the risk of adverse pregnancy outcomes among women with subclinical hypothyroidism (SCH). The aim of this study is to conduct a systematic review and meta-analysis to examine the risk of adverse pregnancy, perinatal, and early childhood outcomes among women with SCH treated with levothyroxine.
A systematic literature search was conducted using Ovid-Medline, Ovid-EMBASE, Pubmed (non-Medline), Ebsco-CINAHL Plus with full text and Cochrane Library databases. Randomized controlled studies (RCTs) and observational studies examining the association between treatment of SCH during pregnancy and our outcomes of interest were included. Studies that compared levothyroxine treatment versus no treatment were eligible for inclusion. Data from included studies were extracted and quality assessment was performed by two independent reviewers.
Treatment of SCH with levothyroxine during pregnancy is associated with decreased risks of pregnancy loss and neonatal death. Given the paucity of available data and heterogeneity of included studies, additional studies are needed to address the benefits of levothyroxine use among pregnant women with SCH.
Subclinical hypothyroidism (SCH) is a common biochemical entity identified in women during pregnancy. SCH is diagnosed when the thyroid stimulating hormone (TSH) is elevated with a normal free thyroxine (FT4) level. Although most women with SCH are asymptomatic, previous studies have shown that SCH may be associated with adverse outcomes during pregnancy [1,2,3].
The thyroid hormone, FT4, is necessary for fetal growth and development. Insufficient thyroid hormone has been shown to impair fetal growth  and brain development  and it may have negative effects on neonatal survival . Women with overt hypothyroidism during pregnancy require levothyroxine treatment . However, there is uncertainty as to whether women with SCH during pregnancy should be treated as the benefits of treating SCH during pregnancy have not been consistently demonstrated [6,7,8,9].
Several studies have examined the association of SCH and adverse outcomes during pregnancy and long-term outcomes in mothers and children including pregnancy loss, pre-term delivery, gestational diabetes, gestational hypertension, eclampsia, placental abruption, low birth weight, and childhood cognitive outcomes [10,11,12,13,14]. Several of these studies reported increased risks of these outcomes among women with untreated SCH during pregnancy [2, 3, 14]. However, there was heterogeneity between studies with respect to the timing of initiation of levothyroxine, the study population, the underlying cause of SCH, and the estimated treatment effects [1, 2, 15, 16]. As a result of the discordant findings, the 2017 American Thyroid Association (ATA) guidelines recommended levothyroxine therapy for women with SCH (defined as a TSH level greater than the pregnancy-specific range) and thyroid autoimmune disease (defined as the presence of anti-thyroid peroxidase antibodies [TPOAb)]). For women with negative TPOAb levels, the guidelines recommended treatment with levothyroxine therapy for TSH levels greater than 10mIU/L.  However, levothyroxine therapy was not recommended for women with no antibodies and a TSH within the pregnancy-specific reference range.
Due to the lack of good quality evidence for treatment of SCH during pregnancy, it is unclear whether levothyroxine treatment should be given to women with isolated SCH during pregnancy . To examine this question, we conducted a systematic review and meta-analysis of studies comparing the risk of maternal and fetal outcomes in women with SCH who were treated or not treated with levothyroxine during pregnancy.
We systematically searched Ovid MEDLINE (Appendix 1), Ovid EMBASE (Appendix 2), Ebsco-CINAHL Plus with Full Text (Appendix 3), Pubmed (for articles not indexed in Medline) (Appendix 4), and Cochrane Library from inception to July 18, 2018 to identify studies that examined the association between treatment of SCH during pregnancy and adverse pregnancy outcomes. A medical librarian (FF) designed and conducted the searches (see Appendix for full search strategies). The Ovid-Medline search was peer reviewed by a second librarian using the Peer Review of Electronic Search Strategies (PRESS) guideline . No language restrictions were applied. We also scanned the references of relevant articles, searched for citing articles (snowballing), and conducted a search of the grey literature to retrieve studies not identified by our primary search. We reviewed previous systematic reviews and meta-analyses of levothyroxine treatment among women with SCH during pregnancy and retrieved studies not identified in our search.
Quality assessment and data extraction were performed for all included studies by two independent reviewers (MB and OY), with disagreements resolved by consensus or by a third reviewer (IK or KBF). The Cochrane Risk of Bias tool was used for RCTs  and the Risk of Bias In Non-randomised Studies of Interventions (ROBINS)-I tool was used for observational studies . We extracted information on study design, study population characteristics (size, demographics, location, study period), SCH definition, key findings, and frequencies and effect estimates and 95% CIs for the association between levothyroxine and adverse pregnancy outcomes. For observational studies, adjusted effect estimates were extracted.
Given the paucity of RCTs that assessed the risk of adverse events during pregnancy with levothyroxine treatment among women with subclinical hypothyroidism, we performed our primary analysis, pooling findings from RCTs and observational studies . By including the totality of evidence in this area of research, we increase precision of our estimates . We also performed a secondary analysis whereby we used meta-regression to study the effects of study design (i.e. RCTs and observational studies) on the association between levothyroxine treatment and pregnancy loss and other adverse outcomes among women with SCH. For each binary outcome, we pooled risk ratios (RR) using Dersimonian and Laird random-effects models with inverse variance weighting , applying the Jackson and Knapp-Hartung extensions [26, 27]. A continuity correction of 0.5 was used for both the treatment and reference groups when a frequency of zero was present. For continuous outcomes, we estimated the weighted mean difference using a similar approach . Heterogeneity was assessed by the tau-squared estimators, and the I2 statistics. We conducted the analyses using the meta package  in R . 2b1af7f3a8