Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Casey, 2017

Type of study: Multicenter Randomized Placebo Controlled Trial

Setting and country:

15

centers within the Eunice Kennedy Shriver National Institute of Child Health and Human

Development Maternal–Fetal Medicine Units Network, USA

Funding and conflicts of interest:

Study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the

National Institute of Neurological Disorders and Stroke. No conflicts of interest were described.

Inclusion criteria:

Women with a singleton pregnancy who presented for prenatal care before 20

weeks of gestation were invited to undergo thyroid screening for serum thyrotropin and free

T4 values. The criteria that were used to diagnose subclinical hypothyroidism at the origin of the trial

were a thyrotropin level of 3.00 mU or more per liter (which was presumed to correspond to

the 97.5th percentile) and a free T4 level in the normal range (0.86 to 1.90 ng per decilitre (11 to 24 pmol per liter)).

Exclusion criteria:

Women who were found to have overt

hypothyroidism or hyperthyroidism at the time of screening were excluded, and obstetrical

providers were notified of abnormal test results for subsequent follow-up.

N total at baseline:

Of the 3057 women with subclinical hypothyroidism, 800 were eligible and consented to participate in the adherence run-in phase, and 677 underwent randomization

Intervention: 339

Control: 338

Important prognostic factors²:

Age ± SD:

I: 27.7± 5.7

C: 27.3 ± 5.7

BMI ± SD

I: 28.1 ± 6.4

C: 28.2 ± 6.4

Thyrotropin –  mIU/L (95% CI)

I: 4.5 (4.4 - 4.7)

C: 4.3 (4.2 - 4.5)

Free thyroxin – ng/dl (95% CI)

I: 1.01 (1.00-1.02)

C: 1.02 (1.01-1.04)

Weeks of gestation ± SD

I: 16.6 ± 3.0

C: 16.7 ± 3.0

Groups comparable at baseline?

Yes, baseline characteristics did not differ significantly between groups. 

100 μg of levothyroxine daily. Women were seen monthly, and blood samples for thyrotropin and free T4 testing were sent to the same laboratory. Results were reported to the coordinating center, which notified the clinical center whether a dose adjustment was required according to the algoritm.

Adjustments were made within 7 days after the blood test. The goal for women with subclinical hypothyroidism was a thyrotropin level between

0.1 and 2.5 mU per liter, with a maximum daily dose of 200 μg of levothyroxine.

100 µg of matching placebo daily. Women were seen monthly, and blood samples for thyrotropin and free T4 testing were sent to the same laboratory. Results were reported to the coordinating center,

which notified the clinical center whether a dose adjustment was required according to the algorithm; for control group sham adjustments were communicated.

Length of follow-up:

Beginning between 8 and 20 weeks of gestation till the age of 5 of the offspring.

Loss-to-follow-up:

Intervention:

16 (5%)

Reasons: not described, it was only described that 4 offspring died before the age of 3.

Control:

12 (4%)

Reasons: not described, it was only described that 9 offspring died before the age of 3.

Incomplete outcome data:

Primary outcome:

A total of 11 children had a DAS score substituted for the WPPSI-II.

Intervention:

16 (4%)

4 offspring died before the age of 3.

Control:

12 (3%)

9 offspring died before 3 years of age.

Stillbirth or miscarriage (%)

I: 2 (1)

C: 5 (2)

P-value: 0.28

Preterm birth < 34wk (%)

I: 10 (4)

C: 7 (3)

P-value: 0.47

Preterm birth < 37wk (%)

I: 31 (12)

C: 20 (8)

P-value: 0.11

Preeclampsia (%)

I: 9 (3)

C: 11 (4)

P-value: 0.64

Birth weight <10^th percentile (%)

I: 23 (9)

C: 20 (8)

P-value: 0.68

Full scale IQ (WPPSI-III)

I: 97 (94-99)

C: 94 (92-96)

Effect: 0 (-3 to 2)

P-value: 0.71

DAS-II scores at 36 months

I: 90 (88-93)

C: 90 (87-93)

Effect: 0 (-2 to 3)

P-value: 0.90

This study consisted of two parallel trials. The other trial focused on levothyroxine treatment in subclinical hypothyroidism in pregnant women.

Kim, 2011

Type of study:

Prospective Randomized Trial.

Setting and country:

University-based in

fertility

clinic at the Asan Medical Center, Seoul, South Korea.

Funding and conflicts of interest:

Funding is not mentioned. The authors declared to have no conflict of interest.

Inclusion criteria:

The study population consisted of 64 infertile patients with subclinical hypothyroidism who had undergone 64 IVF/ICSI cycles between March 2006 and September

2009. Subclinical hypothyroidism was defined as an elevated serum TSH level >4.5  mIU/L with a normal FT4 level and without frank symptoms of Hypothyroidism. All subjects had regular ovulatory cycles (duration, 21–35 days). They

were in good health with normal cardiac, hepatic, and renal functions, and

they had experienced spontaneous onset of puberty and normal sexual development. None of subjects had a previous medical history of subclinical and

clinical hypothyroidism.

Exclusion criteria:

Not described

N total at baseline:

Intervention: 32

Control: 32

Important prognostic factors²:

Age (years ± SD)

I: 36.0 ± 2.4

C: 36.1 ±. 2.2

Free T4 (ng/dL ± SD)

I: 1.2±0.2

C: 1.2±0.2

TSH (ml U/L±SD)

I: 6.6±1.7

C: 6.7±1.8

Nullipara (%)

I: 19 (59.4)

C: 18 (56.3)

Infertility duration (months ± SD)

I: 48.0±24.3

C: 44.2±23.6

Groups comparable at baseline?

Yes, baseline characteristics did not differ significantly between groups. 

50 µg LT4 was administered every morning from the first day of controlled ovarian stimulation (COS) and continued up to the day of serum b-hCG measurement.

If pregnancy was confirmed, an

adequate dose of LT4 was given continuously throughout the pregnancy.

No treatment of placebo. However, even in pregnant women included in the control group, an adequate dose

of LT4 was supplemented when overt hypothyroidism was detected during

pregnancy. The LT4 dosage was titrated to reach and thereafter maintain serum

TSH concentrations of<2.5  mIU/L in the first trimester. Serum TSH and FT4 levels were remeasured every 4–6 weeks, and symptoms of clinical

hypothyroidism were investigated on every visit for routine prenatal examination throughout the pregnancy. One of 12 pregnant patients included in the control group was diagnosed

as having overt hypothyroidism at 24 weeks’ gestation, and

she received LT4 treatment throughout the pregnancy.

Length of follow-up:

Throughout pregnancy until delivery.

Loss-to-follow-up:

Intervention: none

0 (0%)

Reasons n.a.

Control: none

0 (0%)

Reasons n.a.

Incomplete outcome data:

Intervention: none described

Reasons n.a.

Control: none described

Reasons n.a.

Miscarriage rate

I: 0 (0/17)

C: 33.3 (4/12)

P-value: 0.021

Preterm birth

I:0 (0/17)

C: 1 (1/12)

P-value: -

Nazarpour, 2018

Type of study:

Single blind randomized controlled trial.

Setting and country:

Prenatal care centers of the Shahid Beheshti University of Medical Sciences, Iran.

Funding and conflicts of interest:

This work was financially supported by

the Research Institute for Endocrine Sciences. The authors declared to have no conflict of interest.

Inclusion criteria:

SCH was defined as a normal FT4I (1 to 4.5) despite an elevated TSH level (2.5 to 10  mIU/L). SCH was defined as a normal FT4I (1 to 4.5) despite a reduced TSH level (,0.1  mIU/L).

Exclusion criteria:

Overthyperthyroidism, overt hypothyroidism and TPOAb positivity and twin pregnancies. Overt hyperthyroidism was defined as a TSH level <0.1  mIU/L and an FT4I >4.5. Overt hypothyroidism was defined as a TSH level >10  mIU/L or TSH level .2.5  mIU/L and an FT4I <1. TPOAb level > 50 IU/mL was considered TPOAb positivity.

N total at baseline:

Intervention: 183

Control: 183

Important prognostic factors²:

Maternal age( years ± SD):

I: 27.0±5.34

C: 26.9±4.74

Gestation at first visit (weeks ± SD)

I: 11.4±4.10

C: 12.2±4.36

History of infertility (%)

I: 9 (4.9)

C: 8 (4.4)

Groups comparable at baseline?

There was no testing on differences between the groups at baseline, but absolute differences were small.

In group A, patients were

treated with an LT4 morning dose of 1 mg/kg/d, initiated 4 to 8 days after the first prenatal visit and maintained throughout pregnancy.

No treatment or placebo.

Length of follow-up:

Throughout pregnancy until delivery.

Loss-to-follow-up:

Intervention:

7 (%)

Reasons not described

Control:

5 (%)

Reasons not described

Incomplete outcome data:

Intervention: none described

Reasons n.a.

Control: none described

Reasons n.a.

Preterm delivery (%)

I: 18 (9.8)

C: 21 (11.5)

P-value: > 0.05

Stillbirth (%)

I: 0

C: 0

P-value: > 0.05

Birth weight (grams ± SD)

I: 3190.82 ± 455.13

C: 3203.1 ± 497.1

P-value: > 0.05

Zhao, 2018

Type of study:

Randomized Controlled Trial

Setting and country: China

Funding and conflicts of interest:

This study is supported by the grant from Shanghai Jiading District

Health and Family Planning Commission. The authors declared to have no conflict of interest.

Inclusion criteria:

Between January 2014 and October 2016, all the women with single pregnancy were invited to undergo thyroid screening (include anti-TPO test) when conducting their first antenatal visit before 10 weeks of gestation. SCH was defined as normal serum free T4 while TSH concentration was upper than 2.5  mIU/L in the first trimester or greater than 3  mIU/L in the second trimester.

The reference values were 0.55–4.78  mIU/L for TSH,

3.1–6.8 pmol/L for FT3 and 10.9–21.7 pmol/L for FT4.

Exclusion criteria:

Women were excluded on previously set exclusion criteria: pre-existing thyroid disease (Hashimoto’s thyroiditis or Graves’ disease n=4), history of thyroid-interfering drug (polyperridone, phenytoin sodium, etc.) used within three months before the visit (n=2), associated with acute or chronic infection (n=2), and iodine deficiency (n=1).

N total at baseline:

98 eligible participants were randomized to three groups. Of these, two participants withdraw their informed consent forms and three subjects were lost during follow-up or delivery at other hospital, so their data were not included. It is not known to which groups those 5 subjects lost to FU belonged.

Intervention A: 31

Intervention B: 31

Control: 31

Important prognostic factors²:

Age (years ± SD):

IA: 27.2±2.3

IB: 27.5±2.1

C: 27.4±2.4

Primiparity (%)

IA: 30 (96.7)

IB: 28 (83.9)

C: 26 (77.4)

BMI ± SD

IA: 26.2±5.3

IB: 26.1±4.9

C: 26.3±5.6

TPOAb+ (%)

IA: 10

IB: 14

C: 6

Groups comparable at baseline?

Yes, baseline characteristics did not differ significantly between the groups.

Group A received levothyroxine on the

second day diagnosed as SCH (8–10 weeks).

Group B administered treatment at the follow-up visit in the second trimester (13–16 weeks).

The levothyroxine regime was set with starting dose of 25 µg/day and adjusted to a maximum 100 µg/day until the TSH concentration decline to <3  mIU/L.

Group C did not receive levothyroxine or another treatment during the whole gestation.

Length of follow-up:

Throughout pregnancy until delivery

Loss-to-follow-up:

This information was only described for the total group, not separately for each group.

Total group:

5 (%)

Reasons: The 98 eligible participants were randomized to three groups. Of these, two participants withdraw their informed consent forms and three subjects were lost during follow-up or delivery at other

hospital, so their data were not included.

Incomplete outcome data:

Intervention:

None

Reasons n.a.

Control:

None

Reasons n.a.

Preterm labor (%)

IA: 1 (3.2)

IB: 6 (19.4)

IC: 6 (19.4)

P-value: 0.107

Pre-eclampsia (%)

IA: 0

IB:2 (6.5)

IC: 4 (12.9)

P-value: 0.118

Low birth weight (%)

IA: 0 (0)

IB: 1 (3.2)

IC: 2 (6.5)

P-value: 0.356

Pregnancy loss (%)

IA: 0 (0)

IB: 1 (3.2)

IC: 1 (3.2)

P-value: 0.599

Alcazar Lazaro, 2019

Type of study:

RCT

Setting and country: Hospital, Spain

Funding and conflicts of interest:

The authors declared to have no conflict of interest.

Inclusion criteria:

pregnant women with their first trimester TSH antenatal screening performed in the Hospital

Severo Ochoa between January the 1st 2015 and August the 31st 2017.

Exclusion criteria:

previous treatment with levothyroxine, overt hypothyroidism, voluntary pregnancy,termination, twin pregnancies, recurrent abortion (more

than 2 previous abortions) and subclinical hypothyroidism (TSH ≥ 5 mcU/mL and normal free thyroxine (fT4)).

Important prognostic factors²:

Age (years ± SD):

I/C: 32.14 ± 5.37

TSH in mcU/ml (1^st trimester):

I: 3.24 ± 0.59

C: 2.53 ± 0.99

FT4 (1^st trimester)

I: 1.08 ± 0.13

C: 1.10 ± 0.12

Groups comparable at baseline?

Yes, baseline characteristics did not differ significantly between groups.

Treatment was started with levothyroxine at an

initial dose of 0.5 µg/kg of body weight and adjusted as needed in the following visits to reach a TSH level below 3 in the second and third trimester of gestation as proposed by guidelines.

No treatment

Length of follow-up:

Throughout pregnancy until 6 months after delivery.

Loss-to-follow-up:

none

Preeclampsia

I:3 (1.9%)

C: 2 (1.4%)

NS (0.72)

Preterm delivery (before week 37)

I:13 (6.2%)

C: 9 (4.4%)

NS (0.40)

Newborn weight (g)

I: 3211.32 ± 474.45

C: 3249.3 ± 446.7

NS (0.456)

Study reference

(first author, publication year)

Describe method of randomisation¹

Bias due to inadequate concealment of allocation?²

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?³

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?⁴

(unlikely/likely/unclear)

Bias due to loss to follow-up?⁵

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?⁶

(unlikely/likely/unclear)

Casey, 2017

Separate randomization sequences were prepared with the use of the simple urn method with stratification according to clinical site. Numbered trial-regimen kits were prepared, and at randomization, each patient was assigned to the next sequentially numbered kit.

Unlikely

Separate randomization sequences were prepared with the use of the simple urn method.

Unlikely

The sham adjustment in doses in the placebo group, implicates blinding of participants to treatment allocation.

Unlikely

Blinding of care providers not mentioned. However, outcome measures are objective.

Unlikely

Assessor blinding not mentioned. However, outcome measures are objective.

Unlikely

Trial outcomes listed in the methods section/study protocol are also reported.

Unclear

Reasons for lost to FU are not described, but % lost to FU did not differ a lot between the groups (5% versus 4%).

Unlikely

Analysis was performed on a intention-to-treat principle.

Kim, 2011

The subjects were randomized by the

use of sealed envelopes and a computer-generated list.

Unlikely

Subjects were randomized by the

use of sealed envelopes and a computer-generated list.

Likely

The control group did not receive any treatment or placebo.

Unclear

Blinding of care providers not mentioned. However, outcome measures are objective.

Unclear

Assessor blinding not mentioned. However, outcome measures are objective.

Unlikely

Trial outcomes listed in the methods section are also reported.

Unlikely

None of the participants was lost to FU.

Unlikely

Participants included in the analysis are exactly those who were randomized into the trial.

Nazarpour, 2018

The subjects were randomly assigned and a computer-generated list was created to achieve

balance across treatment groups using permuted blocks of four.

Unlikely

Subjects were randomly assigned to two groups and a computer-generated list was created to achieve balance across treatment groups using permuted blocks of four. A sealed opaque envelope was allocated to each subject.

Likely

The control group did not receive any treatment or placebo.

Unlikely

The midwife who did not participate in any subsequent phases of the study, was the only person who knew which group each patient belonged to.

Unlikely

The midwife who did not participate in any subsequent phases of the study, was the only person who knew which group each patient belonged to.

Unlikely

Trial outcomes listed in the methods section are also reported.

Unclear

Reasons for lost to FU were not described.

Unlikely

No participants were excluded from the primary intention-to treat analysis for protocol violations. Participants with missing data were excluded from the analysis, but due to low numbers bias is unlikely.

Zhao, 2018

Subjects were 1:1:1

assigned according to random number table.

Unlikely

Subjects were 1:1:1

assigned according to random number table.

Likely

The control group did not receive any treatment or placebo.

Unclear

It was an open label study. However, outcome measures are objective.

Unclear

It was an open label study. However, outcome measures are objective.

Unlikely

Trial outcomes listed in the methods section are also reported.

Unclear

Numbers of lost to FU are not described on group level.

Likely

The data of subjects lost to FU were not included in the analysis and numbers of lost to FU are not described on group level.

Alcarzar Lazaro, 2019

Randomization method not described.

Unclear

Only stated that patients were randomized.

Likely

The control group did not receive any treatment or placebo.

Unclear

Blinding is not described.  

Unclear

Blinding is not described.  

Unlikely

Trial outcomes listed in the methods section are also reported.

Unlikely

None of the participants was lost to FU.

Unlikely

Participants included in the analysis are exactly those who were randomized into the trial.

Auteur en jaartal

Redenen van exclusie

Ma, 2016

Resultaten weergegeven voor effect van screening, niet apart weergegeven voor patiënten die wel/niet behandeld worden met levothyroxine.

Brenta, 2013

Richtlijn (Latin America) zonder zoekstrategie

Chen, 2018

Systematische review – individuele studies meegenomen

Lazarus, 2012

Studie naar effect van screening

Li, 2017

Systematische review – individuele studies meegenomen

Maraka, 2016

Systematische review van prospectieve studies

Nazarpour, 2017

Geen subklinische hypothyroïdie

Nazarpour, 2019

Systematische review – individuele studies meegenomen

Rahman, 2010

De getallen in het artikel (en erratum) lijken niet te kloppen

Rao, 2018

Systematische review – individuele studies meegenomen

Rao, 2019

Systematische review – individuele studies meegenomen

Reid, 2010

Eerdere versie van Reid, 2013

Reid, 2013

Studie naar effect TPO antistoffen

Stagnaro-Green, 2017

Commentaar op Casey 2017

Thompson, 2018

Systematische review – individuele studies meegenomen

Vissenberg, 2012

Systematische review – individuele studies meegenomen

Yamamato, 2018

Systematische review – individuele studies meegenomen