Recurrent Pregnancy Loss and Thyroid Disease

Effect of Levothyroxine Treatment on Pregnancy Outcome in RPL Women With Subclinical Hypothyroidism

The present study is divided into two groups ,one is the patients with subclinical hypothyroidism who has TPO antibody positive women with TSH concentrations > 2.5 mU/L and below the upper limit of the pregnancy specific reference range ,another is TPO antibody negative with TSH concentrations greater than the pregnancy specific reference range and below 10.0 mU/L.The two groups are randomized into either the LT4 treatment group or control group by the use of a computer-generated list.

The aim of our study is to determine whether the use of levothyroxine is beneficial in patients with subclinical hypothyroidism in two groups。

Study Overview

• Status: Unknown
• Conditions: Recurrent Pregnancy Loss
• Intervention / Treatment: Drug: Levothyroxine

Detailed Description

Many studies have stratified the risk imparted by hypothyroidism according to TPOAb status, and consistently show that this risk is higher in TPOAb positive women. Some data also suggest that the adverse impact associated with maternal TSH levels is apparent at lower TSH elevations in women known to be TPOAb positive compared to women who are TPOAb negative. Furthermore, studies suggest a reduction in pregnancy loss when TPOAb positive women are treated with levothyroxine, even when biochemically euthyroid. Intervention trials have not been performed in TPOAb negative women. A etiology analysis process,from June 2010 to June 2015 in The Second Affiliated Hospital of Soochow University, were showed that 22.2% of total 917 cases who had RPL history present as abnormal serum TSH level or positive TPOAb, while 36.6% of 523 cases who repregnancy present as abnormal.This present study is divided into two groups ,one is the patients with subclinical hypothyroidism who hasTPO antibody positive women with TSH concentrations > 2.5 mU/L and below the upper limit of the pregnancy specific reference range ,another is TPO antibody negative with TSH concentrations greater than the pregnancy specific reference range and below 10.0 mU/L.The two groups are randomized into either the LT4 treatment group or control group by the use of a computer-generated list.For the LT4 treatment group, 50μg LT4 (Merck Serono, Geneva,Switzerland) was administered every morning from the first day of diagnosed as subclinical hypothyroidism and continued up to the day of serum β-HCG measurement.If pregnancy was confirmed, levothyroxine dose need to increase 25-30% and be adjusted according to the pregnancy specific reference range ( T1 0.1-2.5mIU/L,T2 0.2-3.0mIU/L, T3 0.3-3.0mIU/L).For the control group ,women with subclinical hypothyroidism are not given any drugs . The aim of our study is to determine whether the use of levothyroxine is beneficial in patients with subclinical hypothyroidism who has TPO antibody positive women with TSH concentrations > 2.5 mU/L and below the upper limit of the pregnancy specific reference range or TPO antibody negative with TSH concentrations greater than the pregnancy specific reference range and below 10.0 mU/L.

• Study Type: Interventional
• Enrollment (Anticipated): 300
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• China
  • Jiangsu
    • Suzhou, Jiangsu, China, 215004
      • Second Affiliated Hospital of Soochow University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 39 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. having a diagnosis of RPL (two or more consecutive or non-consecutive first-trimester losses)
2. be.ing aged 18-39 years at randomisation
3. trying to conceive naturally
4. willing and able to give informed consent

Exclusion Criteria:

1. they were unable to conceive naturally (as confirmed by urinary pregnancy tests) within 1 year of recruitment or before the end of the randomisation period in the trial, whichever came earlier
2. they had antiphospholipid syndrome [lupus anticoagulant and/or anticardiolipin antibodies (immunoglobulin G or immunoglobulin M)]; other recognised thrombophilic conditions (testing according to usual clinic practice) l they had uterine cavity abnormalities (as assessed by ultrasound, hysterosonography, hysterosalpingogram or hysteroscopy)
3. they had abnormal parental karyotype
4. they had other identifiable causes of RPL (tests initiated only if clinically indicated) such as diabetes or systemic lupus erythematosus
5. they had any contraindications to Levothyroxine use

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Obstet Gynecol,SecondSoochowU; Levothyroxine is an orodispersible tablet.For the LT4 treatment group, 50μg LT4 (Merck Serono, Geneva,Switzerland) was administered every morning from the first day of diagnosed as subclinical hypothyroidism and continued up to the day of serum β-HCG measurement.If pregnancy was confirmed, levothyroxine dose need to increase 25-30% and adjusted according to the pregnancy specific reference range ( T1 0.1-2.5mIU/L,T2 0.2-3.0mIU/L, T3 0.3-3.0mIU/L) .	Drug: Levothyroxine; Levothyroxine is an orodispersible tablet.For the LT4 treatment group, 50μg LT4 (Merck Serono, Geneva,Switzerland) was administered every morning from the first day of diagnosed as subclinical hypothyroidism and continued up to the day of serum β-HCG measurement.If pregnancy was confirmed, levothyroxine dose need to increase 25-30% and adjusted according to the pregnancy specific reference range ( T1 0.1-2.5mIU/L,T2 0.2-3.0mIU/L, T3 0.3-3.0mIU/L) .; Other Names: LT4
NO_INTERVENTION: reproductive center,SecondSoochowU; For the control group ,women with subclinical hypothyroidism are not given any drugs .

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gestational week at delivery	The research doctor site telephoned every participant 2 weeks after the expected date of delivery to obtain pregnancy outcome data.	28 weeks
Newborn birth weight	The research doctor site telephoned every participant 2 weeks after the expected date of delivery to obtain newborn birth weight.	at birth
APGAR Score at birth	The APGAR (Appearance, Pulse, Grimace, Activity, Respiration) scale is determined by evaluating the newborn baby on five simple criteria on a scale from zero to two, then summing up the five values thus obtained. The resulting APGAR score ranges from zero to 10.	at birth

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of clinical pregnancy at 6-8 weeks (defined as the presence of a gestational sac, with or without a yolk sac or fetal pole)	The research doctor site telephoned every participant at between 6 and 7 weeks of gestation, to ensure there were arrangements for an ultrasound appointment with her usual carers, before 8 weeks of gestation. If an appointment had not been booked, the research doctor assisted with booking. The research doctor telephoned each participant again between 3 and 5 days after the scheduled date of the ultrasound appointment, to obtain details of the observations of a gestational sac.	8 weeks
Number of ongoing pregnancy at 12 weeks (defined as the presence of a fetal heartbeat)	The research doctor site telephoned each participant between 10 and 12 weeks of gestation, to ensure there were arrangements for an ultrasound appointment with her usual carers, at between 12 and 14 weeks of gestation. As previously, the research doctor assisted with booking an appointment if necessary, and telephoned the participant afterwards to obtain details of variables such as fetal heartbeat. The research doctor also recorded the expected date of delivery at this stage.	12weeks
Number of miscarriage (defined as loss of pregnancy before 28 weeks of gestation).	The research doctor site telephoned each participant before28 weeks of gestation, to obtain their pregnancy outcomes such as miscarriage.	28 weeks

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital of Soochow University
• Investigators: Principal Investigator: ZHANG Hong, Ph.D,M.D, a staff of The Second Affiliated Hospital of Soochow University

Publications and helpful links

General Publications

• Zhu LY, Chen X, Xu ZZ, Xu L, Mao T, Zhang H. Changes and clinical significance of peripheral blood helper T lymphocyte and natural killer (NK) cells in unexplained recurrent spontaneous abortion (URSA) patients after abortion and successful pregnancy. Clin Exp Obstet Gynecol. 2015;42(1):62-6.
• Wu S, Zhang H, Tian J, Liu L, Dong Y, Mao T. Expression of kisspeptin/GPR54 and PIBF/PR in the first trimester trophoblast and decidua of women with recurrent spontaneous abortion. Pathol Res Pract. 2014 Jan;210(1):47-54. doi: 10.1016/j.prp.2013.09.017. Epub 2013 Oct 26.
• Zhang H, Long Q, Ling L, Gao A, Li H, Lin Q. Elevated expression of KiSS-1 in placenta of preeclampsia and its effect on trophoblast. Reprod Biol. 2011 Jul;11(2):99-115. doi: 10.1016/s1642-431x(12)60048-5.
• Mao C, Zhang H, Xiao D, Zhu L, Ding Y, Zhang Y, Wu L, Xu Z, Zhang L. Perinatal nicotine exposure alters AT 1 and AT 2 receptor expression pattern in the brain of fetal and offspring rats. Brain Res. 2008 Dec 3;1243:47-52. doi: 10.1016/j.brainres.2008.09.060. Epub 2008 Oct 2.

Study record dates

Study Major Dates

• Study Start: July 1, 2015
• Primary Completion (ANTICIPATED): December 1, 2017
• Study Completion (ANTICIPATED): June 1, 2018

Study Registration Dates

• First Submitted: February 27, 2017
• First Submitted That Met QC Criteria: April 4, 2017
• First Posted (ACTUAL): April 11, 2017

Study Record Updates

• Last Update Posted (ACTUAL): April 12, 2017
• Last Update Submitted That Met QC Criteria: April 10, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: recurrent pregnancy loss; Subclinical hypothyroidism; Levothyroxine; thyroid stimulating hormone; thyroid peroxidase antibody; Clinical hypothyroidism
• Additional Relevant MeSH Terms: Pathologic Processes; Endocrine System Diseases; Disease Attributes; Thyroid Diseases; Pregnancy Complications; Death; Hypothyroidism; Recurrence; Abortion, Spontaneous; Abortion, Habitual; Fetal Death
• Other Study ID Numbers: The Second Affiliated Hospital

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes