Swedish Iodine in Pregnancy and Development in Children (SWIDDICH) Study (SWIDDICH)

• ClinicalTrials.gov Identifier: NCT02378246
• Recruitment Status: Recruiting
• First Posted: March 4, 2015
• Last Update Posted: August 15, 2018
• Sponsor: Göteborg University
• Collaborator: Sahlgrenska University Hospital, Sweden
• Information provided by (Responsible Party): Göteborg University

Study Description

Brief Summary:

THE ULTIMATE GOAL of this project is to answer the question "In MILD IODINE DEFICIENCY (ID), should 150 μg iodine/day be administered to pregnant women with a normal diet, to attain a normal cognitive development of the fetus or is there no cognitive deficit from mild ID and no extra iodine is needed?". To answer this question, the investigators planned a randomized, placebo-controlled trial of iodine supplementation during pregnancy in Sweden (SWIDDICH) with the follow-up of childrens' COGNITIVE DEVELOPMENT at 18 months, 3.5, 7 and 14 years.

Iodine deficiency (ID) is associated with thyroid morbidity and, especially in children, with impaired cognitive development. Sweden introduced iodine fortification of table salt 1936 and mental retardation due to severe ID is eradicated. Is mild ID during pregnancy also eradicated? If not, is this of importance? A national study performed by the investigators in 2007 showed iodine sufficiency in general population, but there are no pregnancy data. Local studies have raised concerns for mild ID during pregnancy in Sweden and a trans-sectional national study is currently ongoing.

The burning question for Sweden and the whole world is: is mild ID during pregnancy of importance for the developing brain of the fetus? Two large observational studies have shown association between mild ID during pregnancy and lower verbal IQ or educational performance at school-aged children. The world needs a randomized placebo-controlled trial (RTC) comparing the cognitive outcome in children exposed to mild ID during fetal life with children exposed to normal iodine levels during fetal life.

Our HYPOTHESIS is that pregnant women in Sweden have mild ID and that children exposed to mild ID during fetal life have a lower cognitive development, compared to children to mothers taking 150 ug iodine supplementation during pregnancy.

The MAIN AIM of the SWIDDICH trial is to determine if children exposed to mild iodine deficiency (ID) during fetal life achieve worse cognitive development compared to children exposed to normal iodine status reached by maternal iodine supplementation.

Condition or disease	Intervention/treatment	Phase
Thyroid Gland; Node; Pregnancy; Cognitive Developmental Delay	Dietary Supplement: Iodine; Dietary Supplement: Placebo	Not Applicable

Detailed Description:

AIMS

• To determine if children exposed to mild iodine deficiency (ID) during fetal life achieve worse cognitive development compared to children exposed to normal iodine status reached by maternal iodine supplementation.
• To compare urinary iodine concentration (UIC), thyroglobulin (Tg), free tetraiodothyronine (FT4) and thyroid stimulating hormone (TSH) in pregnant women on 150 µg iodine or placebo
• To compare milk iodine concentration (MIC) in colostrum, and TSH in the first 200 newborn children to pregnant women receiving 150 µg iodine or placebo

BACKGROUND

Iodine deficiency increases the risk for hypothyroidism and goiter and during the pregnancy for abortion or cognitive and other abnormalities of the baby. According to the WHO recommendations, UIC during pregnancy should be 150-249 ug/L. In 2007 a national study showed iodine sufficiency in Swedish general population. It is debated whether or not iodine shall be given to pregnant women in iodine sufficient populations.

The research group started this randomized iodine intervention in pregnant women in 2012. The first hypothesis was that iodine supplementation of 150 µg/day is needed during pregnancy in Sweden in order to ensure normal iodine and thyroid hormone status in mothers and newborn children and that pregnant women in Sweden suffer from mild iodine deficiency (ID).

There is a substantial gap of knowledge with regards to whether mild ID during fetal life entails negative consequences on cognition. Two large observational studies have shown association between mild ID during pregnancy and lower IQ or educational performance in school-children. The only two randomized placebo-controlled trials (RCTs) studying mild ID in pregnancy were either too small for safe conclusions to be drawn ( Brucker-Davis et al, n=86), or did not manage to separate groups based on iodine levels (the MITCH study, Melse-Boonstra et al, n=839). The need for a RCT with sufficient sample size remains. This led the research team to form a second hypothesis within the trial: children exposed to mild ID during fetal life have lower cognitive development compared to children to mothers taking 150 ug iodine supplementation during pregnancy. The decision to expand the trial was made and the target number of participants to be recruited increased from 200 to 1275 in order to reach enough power to follow-up the childrens' cognitive development.

METHODS

Design

This is a prospective placebo-controlled trial of children whose mothers got iodine supplement 150 µg/day or placebo (a multivitamin preparation without iodine) during pregnancy (week 10±2 until delivery). The target number participants during pregnancy is 1275 to enable sufficient power in the children follow-up (n=788). The main outcome is intelligence quotient (IQ) at 7 year of age. Cognitive development in children will be also assessed at 18 months, 3.5, and 14 years.

Pregnancy part

Pregnant women from more than ten maternity care centers in Sweden are randomized to daily receive a multivitamin tablet with 150 µg iodine or placebo (multivitamin without iodine). The intervention starts at pregnancy week 8-12 and ends directly post-partum for the first 200 women and at pregnancy week 36±2weeks for the remaining participants. This time point may be adjusted to local circumstances, depending on when during the third trimester the routine visit at maternity care center takes place. Participants are included after the first visit by a midwife. Urine sample for UIC and U-creatinine, and blood sample for thyroid hormones, thyroid stimulating hormone (TSH), thyroglobuline (Tg) and thyroperoxidase antibodies (TPO-ab) are collected and a simple questionnaire is filled in at week 10±2 weeks of pregnancy and placebo/iodine is started. Selenium and iron is also measured. The same measurements are collected in week 25±1 week and week 36±2 weeks. Directly after delivery (within 5 days), MIC and UIC in the first 200 mother as well as UIC and TSH in their newborn child were collected and a simple questionnaire is filled in. Weight, length and APGAR in the child and pregnancy complications are registered. Blood is also frozen for future analyses and access to medical files is accepted.

In parallel 90 healthy female controls from Skaraborg area stratified for age and smoking habits are collected from a randomized sample attained by the Swedish Tax Agency. UIC, u-creatinine, FT4, TSH, Tg, TPO-ab, and samples to be frozen are collected and a questionnaire is filled in. Selenium and iron is analyzed in blood sample from the first 200 pregnant women and from controls. The primary purpose for having a control population is to ascertain that the normal population in the area of Skaraborg is iodine sufficient.

Children follow-up

At 18 months ± 1 month psychomotor development is assessed by means of ASQ (Ages and Stages Questionnaire). At 3,5 years ± 2 months the IQ is measured (WPPSI-IV), behavior is assessed (CBCL questionnaire) and urine is collected for UIC measurement. At 7 years ± 3 months the following are assessed: IQ (WISC IV), motor development (Movement ABC), behavior (CBCL), symptoms related to attention deficit and hyperactivity disorder (ADHD, 5-15 Nordic questionnaire). Additionally, at 7 years ± 3 months urine is collected for UIC measurement, blood sample is taken for thyreoglobulin (Tg), thyroid hormones and deiodinases, and MRI of the brain is performed in a subsample. At 14 years ± 6 months all these, except for the Movement ABC, are repeated. On all occasions information on socio-economic status and other possible confounders are collected by means of questionnaires filled by parents and by children (14 years).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1275 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: The Importance of Iodine During Pregnancy for Future Brain Function : a Randomized Placebo-controlled Trial. Swedish Iodine in Pregnancy and Development in Children (SWIDDICH) Study
• Actual Study Start Date: November 2012
• Estimated Primary Completion Date: June 2025
• Estimated Study Completion Date: June 2032

Arms and Interventions

Arm	Intervention/treatment
Experimental: Iodine containing multivitamin; multivitamin tablet containing 150 ug iodine, 1 tablet daily	Dietary Supplement: Iodine; We use multivitamin tablets one with 150 microgram iodine for Active comparator and one without iodine as placebo
Placebo Comparator: Placebo: non-iodine containing multivitamin; non-iodine containing multivitamin, 1 tablet daily	Dietary Supplement: Placebo; multivitamin tablets without iodine

Outcome Measures

Primary Outcome Measures :

1. Intelligence quotient (IQ) at 7 years, WISC IV [ Time Frame: when the child is at the age of 7 years ± 3 months ]
   Wechsler Intelligence Scale for Children - Fourth Edition; IQ with sub-domains

Secondary Outcome Measures :

1. Psychomotor development at 18 months, ASQ-3 [ Time Frame: when the child is at the age of 18 months ± 1 month ]
   Ages & Stages Questionnaire - Third Edition; a questionnaire filled in by parents
2. Intelligence quotient (IQ) at 3.5 years, WPPSI IV [ Time Frame: when the child is at the age of 3,5 years ± 2 months ]
   Wechsler Preschool and Primary Scale of Intelligence - Fourth Edition; IQ with sub-domains
3. Intelligence quotient (IQ) at 14 years, WISC IV [ Time Frame: when the child is at the age of 14 years ± 6 months ]
   Wechsler Intelligence Scale for Children - Fourth Edition; IQ with sub-domains
4. Behavioral problems at 3.5 years, CBCL [ Time Frame: when the child is at the age of 3,5 years ± 2 months ]
   Child Behavior Checklist questionnaire filled in by parents
5. Behavioral problems at 7 years, CBCL [ Time Frame: when the child is at the age of 7 years ± 3 months ]
   Child Behavior Checklist questionnaire filled in by parents
6. Behavioral problems at 14 years, CBCL [ Time Frame: when the child is at the age of 14 years ± 6 months ]
   Child Behavior Checklist questionnaire filled in by parents
7. ADHD-related problems at 7 years, FTF [ Time Frame: when the child is at the age of 7 years ± 3 months ]
   Nordic Questionnaire 5-15 (FTF) filled in by parents
8. ADHD-related problems at 14 years, FTF [ Time Frame: when the child is at the age of 14 years ± 6 months ]
   Nordic Questionnaire 5-15 (FTF) filled in by parents
9. Motor skills at 7 years, Movement ABC [ Time Frame: when the child is at the age of 7 years ± 3 months ]
   Movement ABC test performed by a physiotherapist
10. Brain development at 7 years, MRI [ Time Frame: when the child is at the age of 7 years ± 3 months ]
    Magnetic Resonance Imaging; manual and automatic volumetry
11. Brain development at 7 years, MRI [ Time Frame: when the child is at the age of 14 years ± 6 months ]
    Magnetic Resonance Imaging; manual and automatic volumetry
12. Urinary iodine concentration (UIC) in the mother, 1st trimester [ Time Frame: 10±2 weeks (pregnancy) ]
13. Urinary iodine concentration (UIC) in the mother, 2nd trimester [ Time Frame: 26±2 weeks (pregnancy) ]
14. Urinary iodine concentration (UIC) in the mother, 3rd trimester [ Time Frame: 36±2 weeks (pregnancy) ]
15. Thyreoglobulin concentration in serum, in the mother, 1st trimester [ Time Frame: 10±2 weeks (pregnancy) ]
16. Thyreoglobulin in serum, in the mother, 2nd trimester [ Time Frame: 26±2 weeks (pregnancy) ]
17. Thyreoglobulin in serum, in the mother, 3rd trimester [ Time Frame: 36±2 weeks (pregnancy) ]
18. Thyroid stimulating hormon concentration in serum, in the mother, 1st trimester [ Time Frame: 10±2 weeks (pregnancy) ]
19. Thyroid stimulating hormon concentration in serum, in the mother, 2nd trimester [ Time Frame: 26±2 weeks (pregnancy) ]
20. Thyroid stimulating hormon concentration in serum, in the mother, 3rd trimester [ Time Frame: 36±2 weeks (pregnancy) ]
21. Free thyroxine concentration in serum, in the mother, 1st trimester [ Time Frame: 10±2 weeks (pregnancy) ]
22. Free thyroxine concentration in serum, in the mother, 2nd trimester [ Time Frame: 26±2 weeks (pregnancy) ]
23. Free thyroxine concentration in serum, in the mother, 3rd trimester [ Time Frame: 36±2 weeks (pregnancy) ]
    Free thyroxine concentration, serum
24. Anti-TPO in the mother, 1st trimester [ Time Frame: 10±2 weeks (pregnancy) ]
    Thyroid peroxidase antibody titer, plasma
25. Anti-TPO in the mother, 2nd trimester [ Time Frame: 26±2 weeks (pregnancy) ]
    Thyroid peroxidase antibody titer, plasma
26. Anti-TPO in the mother, 3rd trimester [ Time Frame: 36±2 weeks (pregnancy) ]
    Thyroid peroxidase antibody titer, plasma
27. B12 in the mother, 1st trimester [ Time Frame: 10±2 weeks (pregnancy) ]
    Vitamin B12, serum
28. B12 in the mother, 2nd trimester [ Time Frame: 26±2 weeks (pregnancy) ]
    Vitamin B12, serum
29. B12 in the mother, 3rd trimester [ Time Frame: 36±2 weeks (pregnancy) ]
    Vitamin B12, serum
30. Selenium in the mother, 1st trimester [ Time Frame: 10±2 weeks (pregnancy) ]
    Selenium, serum
31. Selenium in the mother, 2nd trimester [ Time Frame: 26±2 weeks (pregnancy) ]
    Selenium, serum
32. Selenium in the mother, 3rd trimester [ Time Frame: 36±2 weeks (pregnancy) ]
    Selenium, serum
33. Iron in the mother, 1st trimester [ Time Frame: 10±2 weeks (pregnancy) ]
    Iron, serum
34. Iron in the mother, 2nd trimester [ Time Frame: 26±2 weeks (pregnancy) ]
    Iron, serum
35. Iron in the mother, 3rd trimester [ Time Frame: 36±2 weeks (pregnancy) ]
    Iron, serum
36. Milk iodine concentration (MIC) in colostrum [ Time Frame: within 5 days after delivery ]
37. Urinary iodine concentration (UIC) in the newborn [ Time Frame: within 5 days after delivery ]
38. Urinary iodine concentration (UIC) in the mother [ Time Frame: within 5 days after delivery ]
39. Urinary iodine concentration (UIC) at 3.5 years [ Time Frame: when the child is at the age of 3,5 years ± 2 months ]
40. Urinary iodine concentration (UIC) at 7 years [ Time Frame: when the child is at the age of 7 years ± 3 months ]
41. Urinary iodine concentration (UIC) at 14 years [ Time Frame: when the child is at the age of 14 years ± 6 months ]
42. Thyroid stimulating hormone, dry blood spot (DBS), in the newborn [ Time Frame: within 5 days after delivery ]
43. TSH at 7 years [ Time Frame: when the child is at the age of 7 years ± 3 months ]
    Thyroid stimulating hormone, dry blood spot (DBS)
44. TSH at 14 years [ Time Frame: when the child is at the age of 14 years ± 6 months ]
    Thyroid stimulating hormone, dry blood spot (DBS)
45. TG at 7 years [ Time Frame: when the child is at the age of 7 years ± 3 months ]
    Thyreoglobulin, dry blood spot (DBS)
46. TG at 14 years [ Time Frame: when the child is at the age of 14 years ± 6 months ]
    Thyreoglobulin, dry blood spot (DBS)
47. FT4 at 7 years [ Time Frame: when the child is at the age of 7 years ± 3 months ]
    Free thyroxine, dry blood spot (DBS)
48. FT4 at 14 years [ Time Frame: when the child is at the age of 14 years ± 6 months ]
    Free thyroxine, dry blood spot (DBS)
49. Deiodinases at 7 years [ Time Frame: when the child is at the age of 7 years ± 3 months ]
    Dry blood spot (DBS)
50. Deiodinases at 14 years [ Time Frame: when the child is at the age of 14 years ± 6 months ]
    Dry blood spot (DBS)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 40 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

PREGNANT WOMEN

Inclusion criteria

• Pregnant, week <12
• Age 18-40 years
• Intent of a full term pregnancy
• Agreement of taking no iodide containing supplements during the study except for study supplement

Exclusion Criteria

• Known current thyroid disease
• Risk factors for thyroid disease (history or heredity for thyroid, other autoimmune disease or symptoms of hypo-/hyperthyroidism) where the TSH is abnormal
• Possibility to not attend to the protocol according to the investigator's opinion
• Less than 6 months from previous pregnancy or lactating period
• Vegan

CONTROL WOMEN

Inclusion criteria

• Age 18-40 years
• Agreeing not to take iodide containing supplements 1 week prior to the collecting of the samples.

Exclusion criteria

• Current thyroid disease
• Risk factors for thyroid disease (history or heredity for thyroid or other autoimmune disease or symptoms of hypo-/hyperthyroidism) where the TSH is abnormal
• Possibility to not attend to the protocol according to the investigator's opinion
• Currently pregnant or lactating
• Less than 6 months from previous pregnancy or lactating period
• Vegans

Contacts and Locations

Contacts

Contact: Sofia Manousou, PhD student; +46700595310; sofia.manousou@vgergion.se

Contact: Helena Filipsson, Ass Prof; 0046-705833398; helena.nystrom@vgregion.se

Locations

Sweden

Umeå Universitet, Department of Clinical Sciences; Recruiting

Umea, Västerbotten, Sweden, 901 85

Contact: Magnus Domellöf, Professor 090-7852128 magnus.domellof@umu.se

Contact: Anna Chmielewska, MD, PhD 090-7852370 anna.chmielewska@umu.se

Sahlgrenska University Hospital; Recruiting

Gothenburg, Sweden, 413 45

Contact: Helena Filipsson, MD, PhD 0705-833398 helena.filipsson@gu.se

Contact: Sofia Manousou, MD 0700-5953310 sofia.manousou@vgregion.se

Sub-Investigator: Lena Hulthén, Senior Prof

Sub-Investigator: Robert Eggertsen, Prof

Principal Investigator: Helena Filipsson Nyström, Ass Prof

Sub-Investigator: Carl-Johan Törnhage, Docent

Sub-Investigator: Birgitta Johansson, Docent

Sub-Investigator: Helge Malmgren, Senior Prof

Linköping University Hospital; Not yet recruiting

Linkoping, Sweden

Contact: Kerstin Gutefeldt

Completed

Skövde, Sweden

Sponsors and Collaborators

Göteborg University

Sahlgrenska University Hospital, Sweden

Investigators

• Principal Investigator: Helena Filipsson Nyström, Ass Prof; Center for Endocrinology and Metabolism, SAhlgrenska University Hospital

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Manousou S, Johansson B, Chmielewska A, Eriksson J, Gutefeldt K, Tornhage CJ, Eggertsen R, Malmgren H, Hulthen L, Domellöf M, Nystrom Filipsson H. Role of iodine-containing multivitamins during pregnancy for children's brain function: protocol of an ongoing randomised controlled trial: the SWIDDICH study. BMJ Open. 2018 Apr 10;8(4):e019945. doi: 10.1136/bmjopen-2017-019945.

• Responsible Party: Göteborg University
• ClinicalTrials.gov Identifier: NCT02378246
• Other Study ID Numbers: 13031305
• First Posted: March 4, 2015
• Last Update Posted: August 15, 2018
• Last Verified: August 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: This has not yet been discussed by the study group.

Keywords provided by Göteborg University:

Iodine; Double-Blind Method; Randomized Controlled Tria; Cognitive Development