AIMS
To determine if children exposed to deficient micronutrition including 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 investigate the interaction between iodine, selenium and iron, as components of
the intervention.
To compare urinary iodine concentration (UIC), thyroglobulin (Tg), free
tetraiodothyronine (FT4) and thyroid stimulating hormone (TSH) in pregnant women on
daily tablet with vitamins and minerals, including 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 daily tablet with vitamins and
minerals, including 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 daily supplementation with a tablet with vitamins and
minerals including 150 µg iodine 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 deficient micronutrition including mild ID during fetal life have lower cognitive
development compared to children to mothers taking a daily tablet with vitamins and
minerals including150 ug iodine 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 (a tablet with vitamins and minerals) or placebo (a multivitamin
preparation without minerals) 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 3.5 year of age.
Cognitive development in children will be also assessed at 18 months, 7, 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 minerals, including 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/intervention is started. Selenium and iron are 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 will be 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).