Introduction

Iodine is required for thyroid hormone synthesis. Because of increased thyroid hormone production, increased renal iodine excretion, and fetal iodine requirements, dietary iodine requirements are higher in pregnancy than they are for non-pregnant women (1). As such, severe iodine deficiency in pregnancy can lead to maternal and fetal hypothyroidism. As adequate thyroid hormone is required for normal fetal development, iodine deficiency in pregnancy is associated with congenital anomalies, decreased intelligence, and cretinism as well as maternal and fetal goitre. Salt iodization is a simple, cheap, and effective means to ensure iodine intake, however large-scale iodization programmes have yet to be implemented in many settings, and despite major progress over the last four decades, it has been estimated that nearly 2 billion individuals worldwide remain at risk for iodine deficiency disorders (2). In many countries, pregnant women in particular are not receiving adequate iodine (3). In settings where iodized salt is not readily available, supplementation may provide needed iodine during pregnancy and lactation.

Methodology summary

This commentary provides an overview of four systematic reviews examining the effects of iodine supplementation in pregnancy (4-7). The review by Bougma et al. (4) included articles which described maternal iodine exposures during pregnancy, had a control group, and assessed child mental development at age ≤5 years. Included studies were either randomized or non-randomized clinical trials of iodine supplementation, or prospective cohorts stratified by iodine status. The review by Zhou et al. (5) was more narrowly focused to include only randomized clinical trials describing the effects of maternal iodine supplementation vs. no supplementation or placebo. The primary outcome was child cognitive development; secondary outcomes included pregnancy and birth outcomes, child growth, child mortality, child iodine status, and thyroid function. The review by Taylor et al. (6) examined randomized clinical trials and observational studies of iodine supplementation for pregnant women in regions of mild to moderate iodine deficiency. Outcomes considered included maternal and neonatal thyroid function and thyroid volume as well as child neurodevelopment. Finally, the Cochrane Review by Harding et al. (4) included randomized or quasi-randomized trials of maternal iodine supplementation in preconception, pregnancy, or the postpartum period, and considered outcomes including maternal and infant thyroid function and thyroid autoimmunity, perinatal mortality, preterm delivery, birth weight, and maternal digestive intolerance.

Evidence summary

The Bougma et al. review (4) included 24 studies, of which 10 were non-randomized intervention studies and two were randomized clinical trials. The quality of most studies was poor as they were largely carried out in the 1960s and 1970s, prior to the development of modern trial methodology. The included studies of maternal iodine supplementation employed high-dose iodized oil injections. Average effect sizes (standardized mean differences) for mental development in children were 0.68 for the two RCTs, 0.46 for the 8 non-randomized interventional studies, 0.52 for nine cohorts stratified by maternal iodine status, and 0.54 for four cohorts stratified by infant iodine status. This translates into an IQ increase of 6.9-10.2 points for children of iodine-supplemented mothers compared to children whose mothers did not receive supplementation. The review by Zhou et al. (5) included 14 publications involving eight randomized clinical trials. Included trials were not adequately blinded or randomized. Only two of the trials reported on child developmental outcomes; one of these (8) clearly demonstrated that maternal iodine supplementation in severely iodine deficient regions substantially reduces or eliminates the risk for cretinism. The six remaining trials, conducted in mildly to moderately iodine deficient regions, did not assess child development, growth, or pregnancy outcomes, and effects on maternal thyroid function were mixed. One of two trials demonstrated decreased maternal thyroid volumes in iodine-supplemented women compared to controls, and decreased infant thyroid volumes in children of supplemented mothers were seen in both trials which examined this outcome. The review by Taylor et al. (6) included seven randomized clinical trials on the effects of maternal iodine supplementation and eight observational studies. The maternal supplementation trials were all conducted in Europe, employed oral iodine doses of 50-300 mcg daily, and were of low to moderate quality. Iodine supplementation was associated with increases in maternal urinary iodine concentrations and decreases in maternal thyroid volume. Three of five trials demonstrated beneficial effects of iodine supplementation on maternal thyroid function, with the other two showing no effect. However, one observational study demonstrated an association between lower maternal thyroid function and self-reported use of iodine supplements >200μg/day, and another demonstrated mildly decreased thyroid function in women who started iodine supplements in early gestation compared to women with long-term consumption of iodized salt. One randomized clinical trial and four observational studies assessed the effects of maternal iodine supplementation on child neurodevelopment; none observed differences in mental development scales but all were limited by low to moderate study quality. The review by Harding et al. (7) included 11 trials conducted between 1966 and 2011 in regions ranging from mildly to severely iodine deficient. Most trials used daily oral iodine doses of 75-300 μg, but four trials employed single high-dose (400-1600 μg) oral or injected iodized oil treatments. In three trials performed in mildly-moderately iodine deficient regions, iodine supplementation during pregnancy was associated with a decreased risk for postpartum maternal hyperthyroidism (average relative risk [RR] 0.32; 95% CI: 0.11-0.91), but increased rates of gastrointestinal intolerance (average RR 15.33; 95% CI: 2.07-113.7). In two trials iodine supplementation was associated with a non-significantly decreased risk for perinatal mortality (average RR 0.9; 95% CI 0.44-2.07); the observed neonatal deaths all occurred in a single trial in a severely iodine deficient setting. Risks for maternal and neonatal hypothyroidism, thyroid autoimmunity, low birth weight infants, and preterm delivery were not found to differ between supplemented and non-supplemented groups.

Discussion

Applicability of the results

In summary, although the quality of older trials was generally poor, the preponderance of evidence suggests that supplementation of severely iodine deficient pregnant women eliminates cretinism and likely increases average IQ of offspring. The efficacy of iodine supplementation in pregnant women with milder degrees of iodine sufficiency is unclear, although such supplementation generally appears to be safe. Universal salt iodization remains the mainstay of iodine deficiency prevention efforts (9). WHO and UNICEF recommend iodine supplementation during pregnancy and lactation in regions where iodized salt is available to fewer than 50% of households, or in regions where 50-90% of households have access to iodized salt and rapid progress toward universal salt iodization is not being made (10). Supplementation can be accomplished by a single annual oral dose of 400 mg iodine as iodized oil, or a daily oral potassium iodide supplement to ensure total daily iodine intake of 250 µg iodine. These recommendations have not been widely adopted. In recent years only 13-50% of pregnant women in Europe and 20% in the U.S. ingest iodine-containing supplements (11, 12) despite regional guidelines calling for such supplementation (13-15).

Implementation in settings with limited resources

Ensuring that at-risk women receive iodine supplements during the pre-conception period or early in pregnancy is an important goal, but only intended as a temporizing measure. Ideally, women should have adequate intrathyroidal iodine stores (10-20 mg) pre-conception. In order to achieve this, sufficient iodine nutrition should be assured by effective universal salt iodization programmes. Targeted supplementation programmes are more costly than universal salt iodization, cannot be readily implemented pre-conception when pregnancies are unplanned, and can be particularly challenging to implement in low-resource regions without strong antenatal care delivery (16).

Further research

High-quality randomized clinical trials are needed to understand the effects of maternal supplementation in mild to moderate deficiency. However, such trials may be challenging to carry out, especially in regions where recommendations for iodine supplementation in pregnancy already exist. Studies are also needed to better define safe upper iodine intake limits in pregnant women, to develop new biomarkers for the assessment of iodine status (17), and to determine how best to assess the neurodevelopmental effects of iodine deficiency (18, 19).

References

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2. Zimmermann MB. The effects of iodine deficiency in pregnancy and infancy. Paediatric and Perinatal Epidemiology. 2012;26(Suppl 1):107-117.

3. Global iodine scorecard and map. Iodine Global Network. 2016. (http://www.ign.org/scorecard.htm)

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5. Zhou SJ, Anderson AJ, Gibson RA, Makrides M. Effect of iodine supplementation in pregnancy on child development and other clinical outcomes: a systematic review of randomized controlled trials. American Journal of Clinical Nutrition. 2013;98:1241-1254.

6. Taylor PN, Okosieme OE, Dayan CM, Lazarus JH. Therapy of endocrine disease: Impact of iodine supplementation in mild-to-moderate iodine deficiency: systematic review and meta-analysis. European Journal of Endocrinology. 2013;170:R1-R15.

7. Harding KB, Peña-Rosas JP, Webster AC, Yap CM, Payne BA, Ota E, De-Regil LM. Iodine supplementation for women during the preconception, pregnancy and postpartum period. Cochrane Database Syst Rev. 2017;3:CD011761.

8. Pharoah PO, Buttfield IH, Hetzel BS. Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy. Lancet. 1971;1(7694):308-310.

9. WHO, ICCIDD, UNICEF. Assessment of iodine deficiency disorders and monitoring their elimination: A guide for programme managers, 3rd. edition. Geneva: World Health Organization; 2007. (http://www.who.int/nutrition/publications/micronutrients/iodine_deficiency/9789241595827/en/)

10. WHO, UNICEF. Reaching optimal iodine nutrition in pregnant and lactating women and young children. Geneva: World Health Organization; 2007. (http://www.who.int/nutrition/publications/micronutrients/WHOStatement__IDD_pregnancy.pdf)

11. Zimmermann MB. Iodine supplementation of pregnant women in Europe: a review and recommendations. European Journal of Clinical Nutrition. 2004;58:979-984.

12. Gregory CO, Serdula MK, Sullivan KM. Use of supplements with and without iodine in women of childbearing age in the United States. Thyroid. 2009;19:1019-1020.

13. Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2016 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease during Pregnancy and the Postpartum. Thyroid. 2017;27(3):315-389.

14. Lazarus J, Brown RS, Daumerie C, Hubalewska-Dydejczyk A, Negro R, Vaidya B. European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. European Thyroid Journal. 2014;3(2):76-94.

15. Council on Environmental Health. Iodine deficiency, pollutant chemicals, and the thyroid: new information on an old problem. Pediatrics. 2014;133(6):1163-1166.

16. Untoro J, Timmer A, Schultink W. The challenges of iodine supplementation: a public health programme perspective. Best Practice & Research Clinical Endocrinology & Metabolism. 2010;24:89-99.

17. Pearce EN, Caldwell KL. Urinary iodine, thyroid function, and thyroglobulin as biomarkers of iodine status. American Journal of Clinical Nutrition. 2016;104 Suppl 3:898S-901S.

18. Bell MA, Ross AP, Goodman G. Assessing infant cognitive development after prenatal iodine supplementation. American Journal of Clinical Nutrition. 2016;104 Suppl 3:928S-934S.

19. Bauer PJ, Dugan JA. Suggested use of sensitive measures of memory to detect functional effects of maternal iodine supplementation on hippocampal development. American Journal of Clinical Nutrition. 2016;104 Suppl 3:935S-940S.

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The named authors alone are responsible for the views expressed in this document.

Declarations of interests

Conflict of interest statements were collected from all named authors and no conflicts were identified.