Spyridoula Maraka,1,2 Naykky M. Singh Ospina,1,2 Derek T. O’Keeffe,1
Ana E. Espinosa De Ycaza,1 Michael R. Gionfriddo,2,3 Patricia J. Erwin,4
Charles C. Coddington III,5 Marius N. Stan,1 M. Hassan Murad,2,6 and Victor M. Montori1,2
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 Con- trolled 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.
Subclinical hypothyroidism (SCH) is defined as an elevated thyrotropin (TSH) concentration with normal serum levels of thyroxine (T4). Historically, the prevalence of SCH during pregnancy in the United States ranged from 2% to 2.5%. In contrast, overt hypothyroidism (OH; elevated TSH, low T4) has a prevalence of 0.2–0.5% (1). Recently, the normal range of TSH during pregnancy was redefined to an upper limit of 2.5mIU/L during the first trimester and 3.0 mIU/L during the second and third trimesters (2). Applying the current diagnostic criteria, 15% of pregnant women in the United States have SCH, a fivefold increase in the prevalence of SCH (3).
In comparison with OH where there is clear evidence for adverse events, the impact of SCH on pregnancy is unclear (4). Multiple studies have reported an association of SCH with an increase in the risk of adverse pregnancy and neo- natal outcomes, including pregnancy loss, preterm delivery, gestational diabetes, gestational hypertension, preeclamp- sia, placental abruption, premature rupture of membranes, intrauterine growth restriction, low birth weight, small for
gestational age, low Apgar score, and neonatal death (5–16). Furthermore, high TSH levels in women during pregnancy have been associated with an increased risk of neurocog- nitive deficits in the offspring (17). Other studies, however, have not found any adverse outcomes associated with SCH (18–21). Moreover, there is uncertainty regarding the im- pact of levothyroxine replacement on improving outcomes in pregnant women with SCH (4). A previous systematic review in 2011 included five articles reporting on the ad- verse outcomes associated with SCH, and the meta-analysis included a maximum of three studies for each of the eval- uated outcomes (22). In 2013, a Cochrane review on inter- ventions for SCH during pregnancy did not identify any studies evaluating the effectiveness of levothyroxine ther- apy on maternal and neonatal outcomes (23). Since the publication of those two reviews, more studies have become available, which justifies a new quantitative synthesis of the available evidence.
A systematic review was therefore conducted, summariz- ing the evidence for the adverse clinical impact of SCH during pregnancy and for the value of levothyroxine therapy in mitigating that impact.
1Division of Endocrinology, Diabetes, Metabolism, and Nutrition; 2Knowledge and Evaluation Research Unit; 3Mayo Graduate School; 4Mayo Clinic Libraries; 5Department of Obstetrics and Gynecology; 6Division of Preventive, Occupational, and Aerospace Medicine; Mayo Clinic, Rochester, Minnesota.
SUBCLINICAL HYPOTHYROIDISM IN PREGNANCY Methods
A systematic review and meta-analyses were performed to estimate (i) the impact of SCH compared to euthyroidism on maternal and neonatal outcomes in pregnant women, and (ii) the efficacy of levothyroxine therapy in preventing ad- verse maternal and neonatal events in pregnant women with SCH. This report follows a review protocol adhering to current standards for reporting of systematic reviews (24).
To assess the impact of SCH on maternal and neonatal outcomes, randomized trials and cohort studies were sought that compared pregnant women with SCH to euthyroid preg- nant women. Participants were pregnant women who had thyroid function tests during pregnancy to determine their thyroid status. SCH was defined as an elevated TSH concen- tration with normal serum T4 level (either total of free) or as an elevated TSH concentration between 2.5 and 5mIU/L. To determine the impact of levothyroxine therapy, randomized trials and cohort studies were sought that compared pregnant women with SCH who received levothyroxine replacement therapy to those who did not. Studies in which the required information to determine eligibility was not available in the manuscript and where no response from the authors seeking that information was obtained were excluded. Studies that reported on a mixed population of SCH and OH during pregnancy were also excluded.
The main outcome measure was pregnancy loss (miscar- riage, intrauterine death, fetal loss). Other outcomes included: preterm labor (onset of labor £37 weeks’ gestation), preterm delivery (delivery £37 weeks’ gestation), gestational hyper- tension (variously defined), preeclampsia (variously defined), eclampsia (variously defined), gestational diabetes (variously defined), placental abruption (premature separation of a nor- mally implanted placenta), placenta previa (placental com- pletely or partially covering the internal cervical os), premature rupture of membranes (PROM; variously defined), cesarean delivery, intrauterine growth restriction (IUGR; variously de- fined), low birth weight (£2500g), low Apgar score (£7 at 5 min), small for gestational age (variously defined), and neo- natal death (variously defined). Pregnancy loss was chosen as the main outcome because it is an outcome important to pa- tients (25) that has significant consequences for pregnant women.
A comprehensive search from each database’s inception to January 2015 was conducted with no language restrictions. The databases included Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, the Cochrane Controlled Trials Register, Ovid EMBASE, Web of Science, and Scopus. An experienced librarian (P.J.E.) designed the search strategy with input from the study’s principal inves- tigator (S.M.). Controlled vocabulary supplemented with keywords was used to search for studies of SCH during pregnancy. The search strategy is available in Appendix 1. The reference list of narrative reviews was reviewed, and experts were consulted to identify additional references.
The search results were uploaded into a systematic review software (DistillerSR, Ottawa, Canada). Reviewers working
independently and in duplicate reviewed all abstracts and titles for inclusion. After abstract screening and retrieval of potentially eligible studies, the full-text publications were assessed for eligibility with excellent chance-adjusted inter- reviewer agreement (j statistic=0.87). Duplicate studies were excluded. Disagreements were resolved by consensus.
Data collection and management
Reviewers working independently and in duplicate using a standardized web-based form collected the following infor- mation from each eligible study: (i) baseline clinical features: gestational age at screening, race/ethnicity, body mass index (BMI), history of smoking, previous pregnancy, pregnancy loss, and preterm delivery, family history of thyroid disease, use of in vitro fertilization/assisted reproduction to achieve the index pregnancy, and educational level; (ii) TSH, T4, and thyroid peroxidase (TPO) antibody levels; (iii) main and other outcomes. The definition of SCH used in each study was also extracted. Disagreements were resolved by discus- sion and consensus. Unclear data were confirmed with the study author when possible.
Risk of bias assessment
The Newcastle-Ottawa risk of bias tool for observational studies was used to evaluate the methodological quality of included studies (26). This tool determines the comparability of the cohorts, their representativeness, and the ascertainment of exposure and outcomes. For the study assessing the impact of levothyroxine on SCH-related pregnancy and neonatal outcomes, risk-of-bias criteria for causal inferences about therapy were adapted (27). Reviewers working indepen- dently assessed the risk of bias of included studies in dupli- cate. Any disagreements were resolved by consensus.
To reduce reporting bias, the authors of studies in which clarification or more information was needed to determine eligibility or to complete analyses were contacted. If no re- sponse was received from an initial e-mail contact, authors were contacted again after a four-week period by e-mail.
Random-effects meta-analyses were conducted using the DerSimonian and Laird method (28) to pool relative risk (RR) and estimate 95% confidence intervals (CI) for each of the outcome measures. Inconsistency was assessed using the I2 statistic, with values <25% indicative of low and >75% indicative of high inconsistency not due to chance (29). Re- view Manager v5.2 was used for statistical analyses (30).
Subgroup and sensitivity analyses
Sensitivity analyses were conducted to explain possible inconsistencies across study results on the main outcome of pregnancy loss. To understand the effect of gestational age at screening for thyroid dysfunction, only studies that included women screened between 0 and 12 weeks of pregnancy (first trimester) and then studies that included women screened at early pregnancy (20th week of gestation or earlier) were analyzed. A sensitivity analysis omitting studies at high risk
MARAKA ET AL.
of bias was planned. Finally, a subgroup analysis was also planned based on the TPO antibody status of the study population.
The search identified 1108 potentially eligible studies, of which 18 cohort studies studying 3995 pregnant women with SCH were eligible (5–8,10–14,18–21,31–35) (Supplementary Fig. S1; Supplementary Data are available online at www .liebertpub.com/thy). One study by Casey et al. from 2005 (5) reported the same outcomes in an overlapping population with Casey et al. from 2007 (12) and was used for sensitivity analysis. Only one eligible observational study assessing the effect of levothyroxine therapy in pregnant women with SCH was found (11).
Table 1 summarizes study characteristics. Due to incon- sistent reporting, it was not possible to present data regarding BMI, history of smoking, history of previous pregnancy, pregnancy loss, and preterm delivery, family history of thy- roid disease, use of in vitro fertilization/assisted reproduction to achieve the index pregnancy, TSH, T4, and TPO antibody levels. Five studies screened women for thyroid dysfunction during the first trimester of pregnancy, and 14 studies screened women during early pregnancy (20th week of ges- tation or earlier). There was no eligible study reporting on eclampsia.
The risk of bias of included studies comparing pregnant women with SCH to euthyroid women was low to moderate, mainly due to limitations in the representativeness of study samples, lack of blinding when assessing the outcomes, and lack of adjustment for confounders (Table 2). The risk of bias of the study assessing the effect of levothyroxine therapy in pregnant women with SCH was high due to lack of ran- domization and blinding.
Table 3 presents the pooled estimates of association be- tween SCH and pregnancy outcomes. Compared with eu- thyroid pregnant women, pregnant women with SCH had a higher risk of pregnancy loss (RR 2.01 [CI 1.66–2.44]; I2 = 0%; Fig. 1A), placental abruption (RR 2.14 [CI 1.23– 3.70]; I2 = 0%), PROM (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 association found for gestational diabetes, preterm labor, preterm delivery, gestational hypertension, pre- eclampsia, placenta previa, cesarean delivery, IUGR, low birth weight, low Apgar score, and small for gestational age.
Wang et al. (11) screened pregnant women in the first trimester (£12 weeks) for thyroid dysfunction. Women with SCH were recommended to start on levothyroxine, but only 14% received therapy. The study found an increased risk of pregnancy loss in pregnant women with SCH compared with euthyroid pregnant women (RR 1.75 [CI 1.12–2.73]). How- ever, comparing 28 pregnant women with SCH who received
levothyroxine replacement therapy to 168 women who did not receive levothyroxine, the study did not find a statistically significant decrease in the rate of pregnancy loss (RR 0.46 [CI 0.12–1.84]), preterm delivery (RR 0.31 [CI 0.02–5.13]), gestational hypertension (RR 3.00 [CI 0.28–31.99]), low birth weight (RR 0.65 [CI 0.04–11.71]), and low Apgar score (RR 0.65 [CI 0.04–11.71]) with levothyroxine therapy. The confidence in these results is limited due to the small sample size and number of events (imprecision), as well as the high risk of bias (most importantly selection bias).
Subgroup and sensitivity analyses
Figure 1B shows the result of the pre-planned sensitivity analysis on gestational age: including only studies in which women were screened for thyroid dysfunction between 0 and 12 weeks of pregnancy (first trimester) resulted in a RR for pregnancy loss of 2.06 [CI 1.66–2.54], while including studies in which women were screened throughout early pregnancy (20th week of gestation or earlier) resulted in an RR of 1.69 ([CI 0.89–3.20]; p-value for difference=0.57). We did not find any studies at high risk of bias for the comparison between pregnant women with SCH and euthy- roid pregnant women. Therefore, no sensitivity analysis was conducted to explore the effects of risk of bias.
In addition to the pre-planned sensitivity analysis, sensi- tivity analyses analyzing the impact of certain decisions made during the conduct of the study were performed. First, a sensitivity analysis was conducted in which the study from Casey et al. from 2007 (12) was replaced with the over- lapping study from Casey et al. from 2005 (5). The analysis revealed similar pooled estimate results (data not shown). Second, a sensitivity analysis in which the unpublished study from Jacob et al. from 2012 (35) was removed resulted in similar pooled estimates (data not shown). Finally, a sensi- tivity analysis was performed in which both the study by Negro et al. from 2010 (6) and Jacob et al. from 2012 (35) were removed on the basis of their different SCH definitions with no significant change in the results (Supplementary Table S1).
Finally, due to insufficient data, it was not possible to perform a subgroup analysis based on the TPO antibody status of the study population.
Summary of evidence
In this systematic review of 18 studies at low-to-moderate risk of bias including 3995 pregnant women with SCH, it was found that pregnant women with SCH were at higher risk for pregnancy loss, placental abruption, PROM, and neonatal death compared with euthyroid pregnant women. Only one observational study on the effect of levothyroxine in pregnant women with SCH was identified, but this study was at high risk of bias and yielded imprecise results.
Limitations and strengths
Incomplete searching and arbitrary study selection repre- sent potential limitations of systematic reviews. However, the rigorous and comprehensive nature of the overlapping search strategies should have minimized the possibility that studies were missed that could substantially change the inferences
drawn from the study. The risk of publication bias is high, particularly when the body of evidence is based on small observational studies. The results of this meta-analysis are driven by 10 larger studies that included >100 pregnant women with SCH. Despite the inconsistency in the gesta- tional age at screening for thyroid function and in the defi- nitions of SCH used, this seemed to contribute little to the variability in the estimates of association, which was mod- erate at worst. Although it would have been clinically meaningful, due to insufficient data, it was not possible to stratify the results by TPO antibody status. Another limitation is the paucity of evidence regarding the effect of levothy- roxine replacement therapy in pregnant women with SCH. Although these limitations cannot be overcome methodol- ogically, this review exhibited important strengths, as the study sought to summarize the totality of the available evi- dence following a predesigned protocol, reproducible judg- ments about study selection and quality, author contact, and focused analyses including an assessment of the effect of gestational age at screening for thyroid dysfunction that has not been performed previously (36).
Implications for practice and research
The present results support an association of SCH during pregnancy with adverse maternal and neonatal outcomes. This association may not be causal, and its magnitude may be overestimated by publication bias. Limitations and variabil- ity in study design reduce confidence in the results, and direct reliable evidence of the extent to which levothyroxine treat- ment in these women could improve pregnancy and neonatal outcomes is not available.
The study shows that there is inconsistency in the definitions of SCH used in the included studies, underscoring the lack of consensus among clinicians and researchers. Currently, in the absence of a laboratory trimester-specific reference range for TSH, a fixed cutoff of 2.5 mIU/L for the first trimester and 3 mIU/L for the second and third trimester is used (2). How- ever, the reference range for TSH and free T4 can vary with geographic area and race/ethnicity (4,37). Indeed, 12/14 recent studies on reference range found that the upper trimester-specific
TSH limit was >2.5 or 3mIU/L, suggesting that a large number of pregnant women could be overdiagnosed with SCH and subsequently be overtreated when using a fixed TSH cutoff (37). Therefore, adapting a population-based reference range could lead to a more accurate diagnosis of SCH. The real challenge is to establish the TSH level above which women experience adverse pregnancy outcomes and levothyroxine therapy prevents these outcomes.
Indirect evidence for the effectiveness of levothyroxine in preventing pregnancy and neonatal complications is provided by one large randomized study designed to compare ‘‘uni- versal screening’’ versus ‘‘case finding’’ in detecting thyroid dysfunction (38). Tests for thyroid function were performed immediately in women who were assigned in the ‘‘universal screening’’ group and in women at the ‘‘case finding’’ group only if there were deemed to be at high risk for thyroid dysfunction. In contrast, the serum samples were frozen and assayed after delivery for women at low risk for thyroid dysfunction in the ‘‘case finding’’ group. Hypothyroid pregnant women who were found to have a TSH >2.5 mIU/L and positive TPO antibody levels were started on levothyr- oxine. The study found that the proportion of hypothyroid women with at least one adverse obstetrical or neonatal outcome was significantly higher in the low-risk ‘‘case finding’’ group (not diagnosed and thus untreated, 91%) compared with the low-risk ‘‘universal screening’’ group (diagnosed and treated, 34%), suggesting a benefit from le- vothyroxine replacement. Moreover, adverse outcomes were less likely to occur among women in the ‘‘universal screen- ing’’ group than among women in the ‘‘case finding’’ group (OR 0.43 [CI 0.26– 0.70]). This effect was driven primarily by adverse outcomes experienced by low-risk hypothyroid women ( p = 0.005) who received treatment in the ‘‘universal screening’’ group but not in the ‘‘case finding’’ group. Given that there was no cutoff for T4 level, this study by design could have included pregnant women with OH who have more severe thyroid dysfunction compared with those with SCH and who are therefore at higher risk for adverse preg- nancy and neonatal outcomes. Finally, the most commonly reported adverse outcome in this study was cesarean delivery with no further clarification as to the indication.
The same group conducted a prospective study where euthyroid TPOAb+ pregnant women were randomly assigned to levothyroxine therapy or no treatment, while TPOAb– pregnant women served as controls (39). The study found that euthyroid pregnant women who were TPOAb+ had an in- creased risk for pregnancy loss, which was mitigated with levothyroxine replacement.
A multicenter randomized trial assessed the impact of levothyroxine on the cognitive function among children of women who had TSH >97.5th percentile or free T4 <2.5th
percentile, or both, during pregnancy (40). The treatment had no effect on the mean offspring IQ at three years or the proportion of children with IQ <85. A post hoc analysis for the subgroup of pregnant women who met the criteria for SCH had the same non-significant results.
Based on the analysis of the concurrent evidence, the American Thyroid Association (ATA) released their guide- lines in 2011; the strength of each recommendation was graded according to the United States Preventive Services Task Force (USPSTF) system. In the USPSTF system, the
SUBCLINICAL HYPOTHYROIDISM IN PREGNANCY
strength of a recommendation is graded A, B, C, D, or I (if insufficient) based on the quality of the evidence (good, fair, poor, insufficient). The ATA guidelines recommend treat- ment of pregnant women with SCH and positive TPO anti- bodies (Level B, fair evidence—USPSTF), but found insufficient evidence to recommend for or against universal levothyroxine treatment in pregnant women with SCH and negative TPO antibodies (Level I—USPSTF) (2). The En- docrine Society, in addition to the USPSTF system, followed the Grading of Recommendations, Assessment, Develop- ment, and Evaluation (GRADE) system to evaluate the strength of each recommendation and the quality of the evi- dence. The Endocrine Society panel recommends levothyr- oxine replacement in all pregnant women with SCH (weak recommendation, low-quality evidence) (41). Implementa- tion of these guidelines will result in diagnosis with SCH and treatment with levothyroxine of up to 15% of pregnant wo- men. The guideline panel acknowledges that the evidence is not sufficient, but focuses on accruing any potential benefit from levothyroxine replacement therapy, noting that any adverse effects such as iatrogenic thyrotoxicosis are rare. However, clinicians and their patients need reliable evidence to decide whether pregnant women with SCH will have better outcomes with levothyroxine replacement therapy.
The uncertainty documented in this review, the variabil- ity in expert recommendations, and the impact on the pregnancy experience of a large proportion of pregnant women underscore the need for randomized trials to esti- mate the effectiveness of levothyroxine therapy in this population, a point that has been emphasized by others (2,22,41,42). An ongoing randomized trial will hopefully offer some answers in the near future (clinicaltrials.gov/ NCT00388297). However, high-risk pregnant women, such as women with multiple gestation pregnancy and with medical comorbidities have been excluded from this trial. Additional trials including high-risk pregnant women as well as women from iodine-deficient areas or with positive TPO antibodies may identify subgroups of patients in whom levothyroxine replacement therapy may be more likely to be beneficial. Moreover, within these trials, different TSH strata should be explored to identify the optimal treatment threshold where the benefits of levothyroxine use outweigh the risks (43). In the meantime, the extent to which 600,000 otherwise normal pregnant women in the United States with laboratory parameters consistent with the current definition of SCH are benefiting from taking levothyroxine therapy is unknown (42). Clinicians and pregnant women with SCH will need to discuss the potential benefits of levothyroxine therapy while taking into consideration the burden of treatment (i.e., daily pills, frequent tests, healthcare visits) and each woman’s preferences and context.
The extant body of evidence supports an association of SCH during pregnancy with multiple adverse maternal and neonatal outcomes, but there is paucity of evidence for the value of levothyroxine therapy to mitigate this association. Clinicians and patients must engage in frank and shared de- cision making while awaiting the results of ongoing efficacy trials and the conduct of larger trials of levothyroxine therapy in high-risk women with SCH during pregnancy.
We are grateful to the authors of primary studies who re- sponded to our requests for data confirmation and missing data (C. Daumerie, J. Walsh, J. Jacob, R. Negro, M. Penin, M. Poulasouchidou, and S. Prema). We would like to thank Dr. Ana Castaneda-Guarderas for technical support. This publi- cation was made possible by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Trans- lational Sciences (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the re- sponsibility of the authors and do not necessarily represent the official view of NIH.
Author Disclosure Statement
The authors have nothing to disclose.
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