# Abstract

 

## Background Concern that mild iodine deficiency in pregnancy may adversely affect neurodevelopment of offspring has led to recommendations for iodine supplementation in the absence of evidence from randomised controlled trials. The primary objective of the study was to investigate the effect of iodine supplementation during pregnancy on childhood neurodevelopment. Secondary outcomes included pregnancy outcomes, maternal thyroid function and general health. 

## Methods Women with a singleton pregnancy of fewer than 20 weeks were randomly assigned to iodine (150 μg/d) or placebo from trial entry to birth. Childhood neurodevelopment was assessed at 18 months by using Bayley Scales of Infant and Toddler Development (Bayley-III). Iodine status and thyroid function were assessed at baseline and at 36 weeks' gestation. Pregnancy outcomes were collected from medical records. 

## Results The trial was stopped after 59 women were randomly assigned following withdrawal of support by the funding body. There were no differences in childhood neurodevelopmental scores between the iodine treated and placebo groups. The mean cognitive, language and motor scores on the Bayley-III (iodine versus placebo, respectively) were 99.4 ± 12.2 versus 101.7 ± 8.2 (mean difference (MD) −2.3, 95 % confidence interval (CI) −7.8, 3.2; *P* = 0.42), 97.2 ± 12.2 versus 97.9 ± 11.5 (MD −0.7, 95 % CI −7.0, 5.6; *P* = 0.83) and 93.9 ± 10.8 versus 92.4 ± 9.7 (MD 1.4, 95 % CI −4.0, 6.9; *P* = 0.61), respectively. No differences were identified between groups in any secondary outcomes. 

## Conclusions Iodine supplementation in pregnancy did not result in better childhood neurodevelopment in this small trial. Adequately powered randomised controlled trials are needed to provide conclusive evidence regarding the effect of iodine supplementation in pregnancy. 

## Trials registration The trial was registered with the Australian New Zealand Clinical Trials Registry at [http://www.anzctr.org.au](#). The registration number of this trial is [ACTRN12610000411044](#). The trial was registered on 21 May 2010. # Results Of the 645 women approached, 205 met the eligibility criteria. A total of 59 out of 205 (29 %) women were enrolled in the study from the Women's & Children's Hospital and the Flinders Medical Centre in Adelaide, Australia, between June 2010 and October 2010 (Fig. [1](#)). Twenty-nine were randomly allocated to iodine and 30 to placebo (Fig. [1](#)). The baseline demographic characteristics of the participants are listed in Table [1](#). The trial was stopped early, before recruitment began in other Australian centres and New Zealand, because the funding body (NHMRC) withdrew its support for the trial. The NHMRC considered a placebo-controlled trial inconsistent with its recommendation for iodine supplementation in pregnancy. The ethics committees did not withdraw approval for the trial, but in view of the funding body's position it supported the trial management committee's decision to unblind the study and to follow all randomly assigned women as planned to monitor safety. Women were informed of their treatment group allocation and were provided with a copy of the NHMRC recommendation for iodine supplementation in pregnancy \[[9](#)\]. All women except two (one from each group) consented to continue with the follow-up after unblinding. The mean gestational age at unblinding was 33 ± 7 weeks. The mean duration of intervention before unblinding was 16 weeks (range 2--23 weeks). Nine (31 %) women in the iodine group and 4 (13 %) in the placebo group gave birth before unblinding. The decision regarding whether to continue taking trial supplements or to take commercially available iodine supplements was at the women's discretion. Five women in the iodine group and 18 in the placebo group stopped taking trial supplements. Only one woman in the placebo group commenced iodine supplements after unblinding. <figure> <p><img src="" /></p> <figcaption>Participant flowchart</figcaption> </figure> ::::table-wrap

::: caption
Baseline demographic characteristics
:::

```
                                                   Iodine (*n* = 29)   Placebo (*n* = 30)
```

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Age at trial entry, years^a^ 29.1 (5.7) 29.8 (5.1)
Gestational age at trial entry, weeks^a^ 15.2 (2.6) 14.9 (2.4)
Primiparous^b^ 13 (44.8) 13 (43.3)
Completed secondary education^b^ 20 (69.0) 22 (73.3)
Completed further education^b^ 22 (75.9) 24 (80.0)
Smoke at trial entry or leading up to pregnancy^b^ 7 (24.1) 5 (16.7)
Miscarriage in previous pregnancy^b^ 8 (27.6) 12 (40.0)
Previous or current depression^b^ 4 (13.8) 7 (23.3)
BMI at trial entry^a^ 25.3 (5.9) 23.6 (3.9)
Pre-pregnancy BMI^a^ 23.6 (5.5) 22.2 (4.3)
Infant sex: male^b^ 20 (71.4) 9 (31.0)

*BMI* body mass index

^a^Data are presented as mean (standard deviation)

^b^Data are presented as number (percentage):::: 

## Neurodevelopment of children The mean composite score of the children did not differ between the iodine and the placebo groups in cognitive (99.4 ± 12.2 versus 101.7 ± 8.2, mean difference (MD): −2.3; 95 % confidence interval (CI) −7.8, 3.2; *P* = 0.42), language (97.2 ± 12.2 versus 97.9 ± 11.5, MD −0.7; 95 % CI −7.0, 5.6; *P* = 0.83) or motor (93.9 ± 10.8 versus 92.4 ± 9.7, MD 1.4; 95 % CI −4.0, 6.9; *P* = 0.61) development (Table [2](#)). Adjustment for sex of the children did not change the outcome (data not shown). There were no differences in the percentage of children with any or moderate/severe developmental delay or in the parent-reported social-emotional behaviours and adaptive behaviour scores between the groups (Table [2](#)). ::::table-wrap
::: caption
Developmental outcomes from the Bayley Scales of Infant and Toddler
Development (Bayley-III)
:::

Outcome Iodine (*n* = 27) Placebo (*n* = 26) Treatment effect (95 % CI) *P* value

______________________________________________________________________

Cognitive Standardised Score^a^ 99.4 (12.2) 101.7 (8.2) −2.3 (−7.8, 3.2) 0.42
Language Standardised Score^a^ 97.2 (12.2) 97.9 (11.5) −0.7 (−7.0, 5.6) 0.83
Motor Standardised Score^a^ 93.9 (10.8) 92.4 (9.7) 1.4 (−4.0, 6.9) 0.61
Social-Emotional Standardised Score^a^ 105.8 (15.9) 105.4 (16.2) 0.4 (−8.5, 9.3) 0.93
Adaptive Behaviour Standardised Score^a^ 105.2 (15.2) 103.5 (14.9) 1.8 (−6.4, 10.0) 0.67
Cognitive score^b^ \<85 1 (3.7) 0 (0.0) N/A >0.99
Cognitive score^b^ \<70 1 (3.7) 0 (0.0) N/A >0.99
Language score^b^ \<85 3 (11.1) 3 (11.5) N/A >0.99
Language score^b^ \<70 0 (0.0) 0 (0.0) N/A N/A
Motor score^b^ \<85 2 (7.4) 5 (19.2) N/A 0.25
Motor score^b^ \<70 1 (3.7) 0 (0.0) N/A >0.99

*CI* confidence interval, *N/A* not applicable

^a^The data are presented as mean (standard deviation), and the
treatment effect is the difference in means

^b^The data are presented as number (percentage):::: 

## Iodine status and thyroid function of mothers and infants The median (interquartile range) UICs of women at baseline (15 weeks' gestation) and at 36 weeks' gestation are shown in Fig. [2](#). The UIC increased from baseline to 36 weeks in the iodine group (median change (interquartile range) from baseline was 87 (−1 to 134) μg/l, *P* = 0.001) but not the placebo group (−2 (−76 to 37) μg/l, *P* = 0.71). The median (interquartile range) breast milk iodine concentration at 6 weeks after birth was 107 (79--147) μg/l overall, and there was no difference in breast milk concentration between the iodine and the placebo group (Table [3](#)). Similarly there were no differences in cord blood fT3, fT4, TSH and Tg concentration between the groups (Table [3](#)). Mean TSH of newborn or percentage of newborn with TSH of more than 5 mU/l from the routine newborn screen test also did not differ between the groups. <figure> <p><img src="" /></p> <figcaption>Median urinary iodine concentration of women. <em>GA</em> gestational age</figcaption> </figure> ::::table-wrap
::: caption
Biomarkers of iodine status
:::

```
                                                    Iodine                Placebo               Effect (95 % CI)   *P* value
```

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Cord blood *n* = 19 *n* = 22\
Free triiodothyronine, pmol/l^a^ 2.3 (0.4) 2.3 (0.6) 0.0 (−0.4, 0.3) 0.81
Free thyroxine, pmol/l^a^ 14.4 (2.1) 13.8 (2.3) 0.6 (−0.9, 2.2) 0.40
Thyroid-stimulating hormone, mIU/l^b^ 8.2 (5.9--13.5) 6.6 (4.5--9.6) N/A 0.25
Thyroglobulin, μg/l^b^ 73.0 (48.0--100.0) 64.0 (44.0--121.0) N/A 0.66
(n = 28) (n = 29)\
Newborn TSH, mIU/l^a^ 2.1 (1.0) 2.2 (1.2) −0.1 (−0.7, 0.5) 0.79
Newborn TSH > 5^c^ 0 (0.0) 0 (0.0) N/A N/A
(n = 20) (n = 25)\
Breast milk iodine at 6 weeks' post-partum, μg/l^b^ 106.0 (84.0--146.0) 124.0 (76.0--155.0) N/A 0.74

*CI* confidence interval, *N/A* not applicable, *TSH*
thyroid-stimulating hormone

^a^Data are presented as mean (standard deviation), and the treatment
effect is the difference in means

^b^Data are presented as median (interquartile range)

^c^Data are presented as number (percentage):::: 

## Pregnancy and other clinical outcomes The mean birth weight, length, head circumference and gestational age at birth did not differ between the groups (Table [4](#)). Adjustment for infant sex did not change the outcome (data not shown). The percentage of infants classified as low birth weight (\<2500 g) or small for gestational age or large for gestational age, or with a neonatal complication or major congenital abnormality, did not differ between the treatment and placebo groups (Table [4](#)). Other pregnancy outcomes, including rate of preterm birth, miscarriage, still birth and antenatal hospital admission, were also not different between the groups (Table [4](#)). ::::table-wrap
::: caption
Pregnancy and neonatal outcomes
:::

```
                                  Iodine                Placebo               Treatment effect (95 % CI)   *P* value
```

______________________________________________________________________

Pregnancy outcome *n* = 29 *n* = 29\
Miscarriage^a^ 1 (3.5) 0 (0.0) N/A >0.99
Stillbirth^a^ 0 (0.0) 0 (0.0) N/A N/A
Caesarean section^a^ 9 (32.1) 5 (17.2) N/A 0.19
Post-term induction^a^ 3 (10.7) 4 (13.8) N/A >0.99
Gestational diabetes^a^ 1 (3.6) 2 (6.9) N/A >0.99
Pregnancy-induced hypertension^a^ 0 (0.0) 0 (0.0) N/A N/A
Pre-eclampsia^a^ 0 (0.0) 0 (0.0) N/A N/A
Antenatal hospital admission^a^ 6 (22.2) 7 (24.1) N/A 0.87
Neonatal outcome n = 28 n = 29\
GA at birth, weeks^b^ 39.3 (37.8 -- 40.4) 39.7 (39.3 -- 40.3) N/A 0.23
Preterm birth, GA \< 37 weeks ^a^ 5 (17.9) 4 (13.8) N/A 0.73
Birth weight, g^c^ 3325.4 (474.7) 3204.3 (689.4) 121.1 (−194.2, 436.3) 0.45
Birth length, cm^c^ 49.4 (2.3) 48.7 (3.3) 0.7 (−0.9, 2.2) 0.37
Birth head circumference, cm^c^ 34.6 (1.3) 33.9 (2.2) 0.7 (−0.3, 1.7) 0.15
Placental weight, g^c^ 533.5 (136.2) 514.4 (129.5) 19.1 (−114.9, 153.2) 0.77
Low birth weight, \<2500 g^a^ 1 (3.6) 3 (10.3) N/A 0.61
SGA^a^ 3 (10.7) 2 (6.9) N/A 0.67
LGA^a^ 2 (7.1) 4 (13.8) N/A 0.67
Major congenital abnormality^a^ 0 (0.0) 0 (0.0) N/A N/A
Neonatal complication^a^ 5 (17.9) 5 (17.2) N/A >0.99
Admission to NICU^a^ 0 (0.0) 2 (6.9) N/A 0.49
Neonatal death^a^ 0 (0.0) 0 (0.0) N/A N/A

*CI* confidence interval, *N/A* not applicable, *GA* gestational age,
*SGA* small for gestational age, *LGA* large for gestational age, *NICU*
neonatal intensive care unit

^a^Data are presented as number (percentage)

^b^Data are presented as median (interquartile range)

^c^Data are presented as mean (standard deviation):::: No women had medically diagnosed depression in pregnancy, and one woman in the iodine group had post-natal depression. There were no differences in the SF-36 or DASS outcomes or the frequency of sweating and palpitation, gastrointestinal side effects or any serious adverse events between the treatment groups (data not shown).


Extracted trial result:
Outcome: The mean motor score on the Bayley-III (continuous)
Intervention: iodine (150 μg/d)
Comparator: placebo
Intervention group size: 27
Intervention mean: 93.9
Intervention standard deviation: 10.8
Comparator group size: 26
Comparator mean: 92.4
Comparator standard deviation: 9.7
Notes: found in table 2