1. Objectives

To evaluate the benefits and harms of iodine supplementation in the preconceptional, pregnancy or postpartum periods on maternal and child outcomes

2. How studies were identified

The following databases were searched in November 2016:

• Cochrane Pregnancy and Childbirth’s Trials Register
• CENTRAL (The Cochrane Library)
• MEDLINE
• EMBASE
• CINAHL
• WHO International Clinical Trials Registry Platform

Reference lists were also searched and the authors directly contacted researchers and organisations in the field

3. Criteria for including studies in the review

3.1 Study type

Randomized and quasi-randomized controlled trials, including cluster-randomized controlled trials

3.2 Study participants

Women prior to pregnancy, pregnant women, and women in the first six weeks postpartum, regardless of iodine status

(Studies that exclusively enrolled women with thyroid disorders or other health problems such as HIV were excluded)

3.3 Interventions

Injected or oral iodine supplementation, with or without other micronutrients, compared with placebo, no intervention, or the same micronutrients without iodine

3.4 Primary outcomes

Maternal - pregnancy and postpartum period

• Hypothyroidism (as defined by trialists)
• Preterm birth (as defined by trialists)
• Adverse effects (elevated thyroid peroxidase antibodies (TPO-ab), hyperthyroidism, digestive intolerance)

Infants and children - to 23 months of age

• Perinatal mortality (stillbirth/fetal death and neonatal death)
• Low birthweight (<2500 g)
• Hypothyroidism or elevated thyroid stimulating hormone (TSH)
• Adverse effects (elevated TPO-ab, hyperthyroidism)

Secondary outcomes for the mother included spontaneous miscarriage, thyroid size, thyroglobulin, insufficient iodine intake (median urinary iodine concentration (UIC) <150 μg/L during pregnancy or <100 μg/L during breastfeeding), and excessive iodine intake in pregnancy (median UIC≥500 μg/L). Secondary outcomes for the child included small-for-gestational age, congenital anomalies (including cretinism), growth, thyroid size, insufficient iodine intake (median UIC<100 μg/L), mental of motor development, and infant death

4. Main results

4.1 Included studies

Eleven of the 14 included trials contributed data to analyses, involving 2737 women

• Two trials recruited postpartum women, two were cluster-randomized and recruited entire families or communities (including pregnant women and women who became pregnant), and 10 trials recruited pregnant women
• Iodine supplementation was provided during pregnancy (7 trials), in the postpartum period (3 trials), during both pregnancy and the postpartum period (4 trials), and in the preconceptional period (2 trials)
• Three trials used single intra-muscular injections of iodized oil (475 to 1600 mg of iodine), and one trial administered a single high-dose oral iodine supplement (400 mg of iodine). The remaining trials used oral supplementation (75 to 300 μg of iodine/day for one to 17 months)
• Three trials supplemented women with additional micronutrients

4.2 Study settings

• Australia, Belgium, Chile, Democratic Republic of the Congo, Denmark, France, Germany, Morocco, New Zealand, Papua New Guinea, Peru, and Thailand
• Most trials recruited pregnant women through antenatal care contacts at clinics or hospitals
• Baseline iodine intake was insufficient in most trials (median UIC 30 to 130 μg/L); three trials reported goitre prevalence (20 to 70%); and one study was reported as being conducted in a setting of endemic cretinism
• Four studies reported on household iodized salt use: three estimated >80% coverage via self-report and one found 57% of salt samples contained some iodine

4.3 Study settings

How the data were analysed
Seven comparisons were planned: i) any iodine supplement versus the same supplement without iodine or no treatment/placebo; ii) any oral iodine supplement versus same supplement without iodine or no treatment/placebo; iii) oral iodine-only supplement versus no intervention or placebo; iv) oral iodine supplement plus other micronutrients versus the same micronutrients without iodine; v) any injected iodine supplement versus the same supplement without iodine or no treatment/placebo; vi) injected iodine-only supplement versus no intervention or placebo; and vii) injected iodine supplement plus other micronutrients versus the same micronutrients without iodine. Random effects meta-analysis was used to generate risk ratios (RR) and corresponding 95% confidence intervals (CI) for dichotomous data, while continuous data were presented as mean differences (MD) and 95% CI. Data from one cluster-randomized trial were already adjusted for clustering, and data from the other cluster-randomized trial were not. In trials with more than two intervention groups, double-counting of the control group was avoided by dividing it between each relevant intervention group in comparisons. The following subgroup analyses were planned, but not conducted, to investigate potential sources of heterogeneity for primary outcomes:

• By period of supplementation: preconception, pregnancy, postpartum, mixed
• By supplementation regimen: daily, weekly, annual/single-dose
• By access to iodized salt: <50%, 50 to 69%, ≥70%, not reported
• By baseline iodine status: adequate, mild-moderate deficiency, severe deficiency, unknown
• By breastfeeding status: ever breastfed, never breastfed, mixed/not reported

Results
Any supplement containing iodine versus the same supplement without iodine or no treatment/placebo
Maternal primary outcomes
No statistically significant difference in the risk of hypothyroidism was found between treatment and control groups in pregnancy (RR 1.90, 95% CI [0.57 to 6.38]; 1 trial/365 women) or the postpartum period (RR 0.44, 95% CI [0.06 to 3.42]; 3 trials/540 women). In two trials involving 376 pregnant women, preterm birth did not differ between treatment groups (RR 0.71, 95% CI [0.30 to 1.66]). The risk of elevated TPO-ab in pregnancy (RR 0.95, 95% CI [0.44 to 2.07]; 1 trial/359 women) or postpartum (RR 1.01, 95% CI 0.78 to 1.30; 3 trials/397 women) was not different between groups. Hyperthyroidism during pregnancy did not differ between groups (RR 1.90, 95% CI [0.57 to 6.38]; 1 trial/365 women), while for postpartum women iodine supplementation reduced the risk by 68% (RR 0.32, 95% CI [0.11 to 0.91]; 3 trials/543 women). In one trial involving 76 pregnant women, iodine supplementation significantly increased the risk of digestive intolerance (nausea and vomiting) (RR 15.33, 95% CI [2.70 to 113.7]).

Infant and child primary outcomes
The risk of perinatal mortality (RR 0.66, 95% CI [0.42 to 1.03], 2 trials/457 participants) and low birthweight (RR 0.56, 95% CI [0.26 to 1.23]; 2 trials/377 infants) were not statistically significantly reduced with iodine supplementation. In two trials including 260 infants, the risk of neonatal elevated TSH did not differ between treatment groups (RR 0.58, 95% CI [0.11 to 3.12]), and in another trial including 108 infants, the risk of elevated TPO-ab also did not differ between groups (RR 0.61, 95% CI [0.07 to 5.70]). No trials reported on the outcome of neonatal hyperthyroidism.

Additional maternal outcomes
Pooled analysis of two trials including 432 pregnant women demonstrated a 36% reduction in the risk of insufficient iodine intake (median UIC<150 μg/L) with iodine supplementation (RR 0.64, 95% CI [0.51 to 0.80]). For postpartum women, the reduction in risk of insufficient iodine intake (median UIC<100 μg/L) was lower, but remained statistically significant (RR 0.81, 95% CI [0.70 to 0.93]; 2 trials/425 women). In one trial involving 356 pregnant women, the risk of excessive iodine intake (median UIC≥500 μg/L) was significantly increased among those receiving iodine (RR 4.33, 95% CI [1.24 to 15.07]). For the maternal outcomes spontaneous miscarriage and goitre, no significant differences between groups were found in pooled analyses. Maternal thyroid volume was lower than or similar to the control group in pregnancy (3 trials, data not pooled) and postpartum (4 trials, data not pooled). All trials reporting on pregnancy or postpartum thyroglobulin found a decrease with iodine supplementation (4 trials, data not pooled).

Additional infant and child outcomes
A 73% reduction in the risk of congenital anomalies was found with iodine supplementation in pooled analysis of two trials, although all reported cases occurred in one trial (RR 0.27, 95% CI [0.12 to 0.60]; 2 trials/875 individuals). In this trial, six of the seven cases in the iodine group occurred among women who received iodine during rather than before pregnancy. Pooled analysis of three trials including 684 neonates demonstrated a reduction in the risk of goitre among those in the treatment group (RR 0.11, 95% CI [0.02 to 0.56]) and neonatal thyroid volume was also lower (MD -0.34 mL, 95% CI [-0.58 to -0.11]; 3 trials/359 neonates). The risk of insufficient neonatal iodine intake (median UIC<100 μg/L) was increased with maternal iodine supplementation in one trial of 159 neonates (RR 2.14, 95% CI [1.04 to 4.37]). In one trial including 149 neonates, three out of eight subscales of the Neonatal Behavioural Assessment Scales were improved with iodine supplementation, three were equal between treatment and control groups, and one was higher in the control group. For child mental or motor development, a higher IQ score was found among children whose mothers received iodine (MD 11.21 IQ points, 95% CI [7.96 to 14.46], 2 trials/174 children). In another trial assessing mental and motor development at 18 months, no differences were found between treatment groups. No difference was found between treatment groups in the risk of small-for-gestational age, and no trials reported on child growth or infant death.

Any oral iodine supplement versus the same supplement without iodine or no treatment/placebo
Maternal outcomes
All results are the same as those presented above under “Any supplement containing iodine versus the same supplement without iodine or no treatment/placebo.”

Infant and child outcomes
In one oral iodine trial including 58 participants, no events were reported for perinatal mortality or congenital anomalies. The risk of neonatal goitre was reduced by 89% with maternal oral iodine supplementation in pooled analysis of two trials (RR 0.11, 95% CI [0.02 to 0.56]; 228 neonates). No trials reported on the outcome neonatal hyperthyroidism. Child IQ was not assessed in oral iodine trials. All other results are the same as those presented above under “Any supplement containing iodine versus the same supplement without iodine or no treatment/placebo.”

Oral iodine-only supplement versus no intervention or placebo
Maternal outcomes
Postpartum hypothyroidism did not differ between treatment and control groups in three trials including 340 women (RR 0.91, 95% CI [0.10 to 8.60]). Oral iodine-only supplementation had no effect on the risk of preterm birth in one small trial including 58 women (RR 1.25, 95% CI [0.37 to 4.19]). The risk of elevated TPO-ab and hyperthyroidism in the postpartum period was not increased with iodine supplementation (RR 0.62, 95% CI [0.15 to 2.51]; 2 trials/162 women; and RR 0.29, 95% CI [0.01 to 7.06]; 2 trials/286 women, respectively). The risk of insufficient iodine intake in the postpartum period was reduced by 19% with iodine supplementation in one trial including 175 women (RR 0.81, 95% CI [0.69 to 0.96]). In one trial including 54 women, maternal thyroid volume and thyroglobulin in pregnancy were lower with iodine supplementation. In two trials including 157 women, thyroglobulin in the postpartum period was lower with iodine supplementation (data not pooled). No other reported outcomes differed between iodine and control groups.

Infant and child outcomes
In one oral iodine-only trial including 58 participants, no events were reported for perinatal mortality, congenital anomalies, or neonatal hypothyroidism, and in the same trial, no significant effect was found for the outcomes low birthweight (RR 0.33, 95% CI [0.04 to 3.02]), or small-for-gestational age (RR 1.50, 95% CI [0.27 to 8.32]). The risk of neonatal elevated TPO-ab did not differ between treatment groups in one trial including 108 participants (RR 0.61, 95% CI [0.07 to 5.70]). Neonatal thyroid volume was reduced with maternal iodine supplementation in two trials including 228 women (MD -0.53 mL, 95% CI [-1.02 to -0.03]). No other reported outcomes were statistically significantly different between treatment groups.

Oral iodine supplement plus other micronutrients versus the same micronutrients without iodine
Maternal outcomes
The risk of maternal hypothyroidism was not affected by iodine supplementation in pregnancy (RR 1.90, 95% CI [0.57 to 6.38]; 1 trial/365 women) or the postpartum period (RR 0.97, 95% CI [0.06 to 15.32]; 1 trial/254 women). Preterm birth did not differ between treatment groups in one trial including 318 women (RR 0.51, 95% CI [0.23 to 1.14]). The maternal adverse effects elevated TPO-ab (pregnancy: RR 0.95, 95% CI [0.44 to 2.07]; 1 trial/359 women; postpartum: RR 1.03, 95% CI [0.79 to 1.33]; 1 trial/235 women) and hyperthyroidism (pregnancy: RR 1.90, 95% CI [0.57 to 6.38]; 1 trial/365 women; postpartum: RR 0.35, 95% CI [0.35 to 1.06]; 1 trial/257 women) did not differ between treatment groups. The risk of digestive intolerance during pregnancy was increased among those receiving iodine supplementation (RR 15.33, 95% CI [2.07 to 113.70]; 1 trial/76 women). While the risk of maternal insufficient iodine intake during pregnancy was reduced with iodine supplementation (RR 0.64, 95% CI [0.51 to 0.80]; 2 trials/432 women), the risk of excessive iodine intake during pregnancy was increased (RR 4.33, 95% CI [1.24 to 15.07]; 1 trial/356 women). Maternal thyroid volume in pregnancy and the postpartum period was lower than or similar to the control group (pregnancy: 2 trials/442 women; postpartum: 2 trials/300 women; data not pooled). Maternal thyroglobulin was reduced in pregnancy (3 trials/508 women) and the postpartum period (2 trials/300 women) with iodine supplementation. No other reported outcomes differed between iodine and control groups.

Infant and child outcomes
Low birthweight (RR 0.61, 95% CI [0.27 to 1.39]; 1 trial/319 infants) and neonatal hypothyroidism (RR 0.58, 95% CI [0.11 to 3.12]; 1 trial/219 infants) did not differ significantly between treatment groups. Neonatal thyroid volume was marginally reduced with maternal iodine supplementation (MD 0.09 mL, 95% CI [-0.18 to 0.00], p=0.044; 1 trial/131 infants). The risk of insufficient neonatal iodine intake was increased with maternal iodine supplementation in one trial of 159 neonates (RR 2.14, 95% CI [1.04 to 4.37]). In one trial including 149 neonates, three out of eight subscales of the Neonatal Behavioural Assessment Scales were improved with iodine supplementation, three were equal between treatment and control groups, and one was higher in the control group. No other reported outcomes differed between treatment and control groups.

Any injected iodine supplement versus the same supplement without iodine or no treatment/placebo
Maternal outcomes
No maternal outcomes were reported in the included trials.

Infant and child outcomes
The risk of perinatal mortality was reduced by 34% with iodine supplementation, although this finding was not statistically significant (RR 0.66, 95% CI [0.42 to 1.03]; 1 trial/399 infants). The risk of congenital anomalies was reduced by 73% in one trial of 818 participants (RR 0.27, 95% CI [0.12 to 0.60]). No other outcomes were reported. No neonatal goitre events occurred in either group in one trial of 456 infants. Child IQ was increased by 11.21 points (95% CI [7.96 to 14.46]) with maternal iodine treatment in two trials of 174 participants.

Injected iodine-only supplement versus no intervention or placebo
All results are the same as those presented above under “Any injected iodine supplement versus the same supplement without iodine or no treatment/placebo.”

Injected iodine supplement plus other micronutrients versus the same micronutrients without iodine
No studies contributed data for this comparison.

5. Additional author observations*

None of the included trials were assessed as being of high quality. For the first comparison, any iodine supplement versus the same supplement without iodine or no treatment/placebo, the quality of evidence according to GRADE criteria was judged as low for all maternal primary outcomes except digestive intolerance, which was judged as very low quality. For child primary outcomes, the quality of evidence was judged as low for perinatal mortality and low birthweight, and very low for neonatal hypothyroidism or elevated TSH, and neonatal elevated TPO-ab. Most data came from settings of mild or moderate iodine deficiency and thus may not be generalizable to settings with severe iodine deficiency.

Iodine supplementation may reduce the risk of postpartum hyperthyroidism but may also increase the risk of digestive intolerance in pregnancy. Due to limited data and low-quality trials, these effects should be interpreted with caution. No clear effect of iodine supplementation was found for other maternal or child primary outcomes.

While more high-quality trials are needed, it may be unethical to conduct such trials in areas of severe iodine deficiency and difficult to conduct trials in settings where iodine is included in prenatal supplements. Future trials should follow children beyond the neonatal period.