Impact of levothyroxine therapy on obstetric, neonatal and childhood outcomes in women with subclinical hypothyroidism diagnosed in pregnancy: a systematic review and meta-analysis of randomised controlled trials

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Abstract

Objective

To determine in women with subclinical hypothyroidism diagnosed in pregnancy whether levothyroxine treatment compared with control, impacts important obstetrical or childhood outcomes (specifically IQ) in randomised controlled trials.

Design

Systematic review and meta-analysis.

Study eligibility criteria

Randomised trials which met all the following were included: (1) reported original data of women with subclinical hypothyroidism diagnosed in pregnancy (by any prespecified study definition); (2) randomised to either levothyroxine or control (placebo or no treatment); (3) reported obstetrical outcomes and/or childhood neurodevelopmental outcomes and (4) published from 1980 to January 2018 in either English or French language.

Data sources

Medline, EMBASE, CINAHL, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov.

Outcome measures

Obstetrical, neonatal and childhood outcomes including: miscarriage, gestational hypertension, pre-eclampsia, preterm delivery, mode of delivery, neonatal intensive care unit admission, birth weight, gestational age at delivery, childhood IQ and neurodevelopmental scores.

Risk of bias assessment

Cochrane Risk of Bias Tool (Modified) for Quality Assessment of Randomised Controlled Trials

Results

Three trials of low to unclear risk of bias with 1837 participants were included. Two studies were meta-analysed for maternal and neonatal outcomes and two studies for childhood IQ. No statistically significant differences were found for any clinical outcomes with levothyroxine therapy compared with control.

Limitations

Only three trials were identified for inclusion.

Conclusions

This review, based on three randomised trials in women with subclinical hypothyroidism diagnosed in pregnancy, found no evidence of benefit of levothyroxine therapy on obstetrical, neonatal, childhood IQ or neurodevelopmental outcomes. Current trial evidence does not support the treatment of subclinical hypothyroidism diagnosed in pregnancy.

PROSPERO registration number

CRD4201707980.

Related collections

Most cited references 27

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Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline.

Leslie De Groot, Marcos Abalovich, Erik Alexander … (2012)

The aim was to update the guidelines for the management of thyroid dysfunction during pregnancy and postpartum published previously in 2007. A summary of changes between the 2007 and 2012 version is identified in the Supplemental Data (published on The Endocrine Society's Journals Online web site at http://jcem.endojournals.org). This evidence-based guideline was developed according to the U.S. Preventive Service Task Force, grading items level A, B, C, D, or I, on the basis of the strength of evidence and magnitude of net benefit (benefits minus harms) as well as the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The guideline was developed through a series of e-mails, conference calls, and one face-to-face meeting. An initial draft was prepared by the Task Force, with the help of a medical writer, and reviewed and commented on by members of The Endocrine Society, Asia and Oceania Thyroid Association, and the Latin American Thyroid Society. A second draft was reviewed and approved by The Endocrine Society Council. At each stage of review, the Task Force received written comments and incorporated substantive changes. Practice guidelines are presented for diagnosis and treatment of patients with thyroid-related medical issues just before and during pregnancy and in the postpartum interval. These include evidence-based approaches to assessing the cause of the condition, treating it, and managing hypothyroidism, hyperthyroidism, gestational hyperthyroidism, thyroid autoimmunity, thyroid tumors, iodine nutrition, postpartum thyroiditis, and screening for thyroid disease. Indications and side effects of therapeutic agents used in treatment are also presented.

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2014 European Thyroid Association Guidelines for the Management of Subclinical Hypothyroidism in Pregnancy and in Children

John Lazarus, Rosalind S. Brown, Chantal Daumerie … (2014)

This guideline has been produced as the official statement of the European Thyroid Association guideline committee. Subclinical hypothyroidism (SCH) in pregnancy is defined as a thyroid-stimulating hormone (TSH) level above the pregnancy-related reference range with a normal serum thyroxine concentration. Isolated hypothyroxinaemia (defined as a thyroxine level below the 2.5th centile of the pregnancy-related reference range with a normal TSH level) is also recognized in pregnancy. In the majority of SCH the cause is autoimmune thyroiditis but may also be due to iodine deficiency. The cause of isolated hypothyroxinaemia is usually not apparent, but iodine deficiency may be a factor. SCH and isolated hypothyroxinaemia are both associated with adverse obstetric outcomes. Levothyroxine therapy may ameliorate some of these with SCH but not in isolated hypothyroxinaemia. SCH and isolated hypothyroxinaemia are both associated with neuro-intellectual impairment of the child, but there is no evidence that maternal levothyroxine therapy improves this outcome. Targeted antenatal screening for thyroid function will miss a substantial percentage of women with thyroid dysfunction. In children SCH (serum TSH concentration >5.5-10 mU/l) normalizes in >70% and persists in the majority of the remaining patients over the subsequent 5 years, but rarely worsens. There is a lack of studies examining the impact of SCH on the neuropsychological development of children under the age of 3 years. In older children, the evidence for an association between SCH and impaired neuropsychological development is inconsistent. Good quality studies examining the effect of treatment of SCH in children are lacking.

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Antenatal thyroid screening and childhood cognitive function.

Arthur B Parkes, M. George, Junaidu Maina … (2012)

Children born to women with low thyroid hormone levels have been reported to have decreased cognitive function. We conducted a randomized trial in which pregnant women at a gestation of 15 weeks 6 days or less provided blood samples for measurement of thyrotropin and free thyroxine (T(4)). Women were assigned to a screening group (in which measurements were obtained immediately) or a control group (in which serum was stored and measurements were obtained shortly after delivery). Thyrotropin levels above the 97.5th percentile, free T(4) levels below the 2.5th percentile, or both were considered a positive screening result. Women with positive findings in the screening group were assigned to 150 μg of levothyroxine per day. The primary outcome was IQ at 3 years of age in children of women with positive results, as measured by psychologists who were unaware of the group assignments. Of 21,846 women who provided blood samples (at a median gestational age of 12 weeks 3 days), 390 women in the screening group and 404 in the control group tested positive. The median gestational age at the start of levothyroxine treatment was 13 weeks 3 days; treatment was adjusted as needed to achieve a target thyrotropin level of 0.1 to 1.0 mIU per liter. Among the children of women with positive results, the mean IQ scores were 99.2 and 100.0 in the screening and control groups, respectively (difference, 0.8; 95% confidence interval [CI], -1.1 to 2.6; P=0.40 by intention-to-treat analysis); the proportions of children with an IQ of less than 85 were 12.1% in the screening group and 14.1% in the control group (difference, 2.1 percentage points; 95% CI, -2.6 to 6.7; P=0.39). An on-treatment analysis showed similar results. Antenatal screening (at a median gestational age of 12 weeks 3 days) and maternal treatment for hypothyroidism did not result in improved cognitive function in children at 3 years of age. (Funded by the Wellcome Trust UK and Compagnia di San Paulo, Turin; Current Controlled Trials number, ISRCTN46178175.).

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Author and article information

Journal

Journal ID (nlm-ta): BMJ Open

Journal ID (iso-abbrev): BMJ Open

Journal ID (hwp): bmjopen

Journal ID (publisher-id): bmjopen

Title: BMJ Open

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2044-6055

Publication date Collection: 2018

Publication date (Electronic): 8 September 2018

Volume: 8

Issue: 9

Electronic Location Identifier: e022837

Affiliations

[1 ] departmentDivision of Endocrinology and Metabolism, Department of Medicine , Cumming School of Medicine, University of Calgary , Calgary, Alberta, Canada

[2 ] departmentDivision of General Internal Medicine, Department of Obstetrics and Gynaecology , Cumming School of Medicine, University of Calgary , Calgary, Alberta, Canada

[3 ] departmentDivision of General Internal Medicine, Department of Medicine , Cumming School of Medicine, University of Calgary , Calgary, Alberta, Canada

[4 ] departmentDivision of Endocrinology and Metabolism, Department of Obstetrics and Gynaecology , Cumming School of Medicine, University of Calgary , Calgary, Alberta, Canada

Author notes

[Correspondence to ] Dr Lois E Donovan; lois.donovan@ 123456albertahealthservices.ca

Article

Publisher ID: bmjopen-2018-022837

DOI: 10.1136/bmjopen-2018-022837

PMC ID: 6129097

PubMed ID: 30196268

SO-VID: c168b283-f229-452b-aac8-85fceabd8ba2

License:

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 08 March 2018

Date revision received : 09 June 2018

Date accepted : 11 July 2018

Custom metadata

special-feature unlocked

ScienceOpen disciplines: Medicine

Keywords: pregnancy,thyroid disease,subclinical hypothyroidism,meta-analysis,clinical practice,randomised control trials

Data availability:

ScienceOpen disciplines: Medicine

Keywords: pregnancy, thyroid disease, subclinical hypothyroidism, meta-analysis, clinical practice, randomised control trials

Impact of levothyroxine therapy on obstetric, neonatal and childhood outcomes in women with subclinical hypothyroidism diagnosed in pregnancy: a systematic review and meta-analysis of randomised controlled trials

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Abstract

Objective

Design

Study eligibility criteria

Data sources

Outcome measures

Results

Limitations

Conclusions

PROSPERO registration number

Related collections

HLA-G and immune tolerance in pregnancy

Most cited references 27

Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline.

2014 European Thyroid Association Guidelines for the Management of Subclinical Hypothyroidism in Pregnancy and in Children

Antenatal thyroid screening and childhood cognitive function.

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