Iodine and Fertility: Do we Know Enough?

Divya M. Mathews; Neil P. Johnson; Robert G. Sim; Susannah O'Sullivan; Jane M. Peart; Paul L. Hofman

Disclosures

Hum Reprod. 2021;36(2):265-274. 

In This Article

Iodine—an Essential Micronutrient for Normal Reproduction

Iodine is a trace element in soil and water and is ingested in several chemical forms. Seaweeds, fish or other seafood, iodized salt and iodinated breads are the main dietary sources of iodine (Leung and Braverman, 2014). Most forms of iodine are reduced to iodide and efficiently absorbed in the stomach and duodenum. Tissue uptake occurs via sodium iodide symporters with main organs in descending order being thyroid, ovaries, uterine endometrium, stomach and breast tissue (Venturi et al., 2000; Mahapatra and Chandra, 2017). In adults, the mean daily turnover of iodine by the thyroid is approximately 60–95 μg. In the thyroid gland, iodide is vital for the enzymatic action of thyroid peroxidase and iodination of thyroglobulin, which are essential steps in thyroid hormone synthesis and release. Under normal circumstances, iodine is cleared from the circulation by the kidneys in approximately 10 h (Chung, 2014).

Daily iodine requirement in a normal adult in the reproductive age group is approximately 150 μg per day, with a higher requirement in pregnancy and breastfeeding (200–250 μg and 200–290 μg, respectively) (Harding et al., 2017). The tolerable upper-level threshold without notable adverse effects is 1100 μg/day (Alexander et al., 2017). Median urine iodine concentrations have been widely used as a biomarker of population iodine intake, with levels >300 μg/l considered excessive in adults and >500 μg/l considered excessive in pregnant women (Leung and Braverman, 2014).

Iodine is listed among the micronutrients required for normal female fertility (Buhling and Grajecki, 2013). Severe iodine deficiency can lead to reduced thyroid hormone production in pregnancy. This can have adverse consequences even with milder abnormalities such as subclinical hypothyroidism. Untreated mild elevation of thyroid-stimulating hormone (TSH) in early pregnancy has been found to be associated with increased risk of miscarriages and adverse perinatal outcome (van den Boogaard et al., 2011; Schneuer et al., 2012).

Maternal iodine also plays a significant role in neurological development of the fetus. It is critical to the synthesis and secretion of the prohormone, thyroxine (T4) and the active hormone triiodothyronine (T3) in the fetus and mother. Maternal iodine deficiency causes increased conversion of T4 to T3, resulting in low maternal T4 levels but a euthyroid state (Greer et al., 1968). As T4 is essential for fetal neurological development, low maternal T4 levels can result in neurocognitive sequelae. In particular, as the fetus is entirely dependent on maternal T4 in early pregnancy, iodine deficiency in the first trimester is an especially vulnerable time (Contempré et al., 1993; Burrow et al., 1994; Calvo et al., 2002). Before successful implementation of iodine fortification, endemic cretinism (defined as goitre with severe irreversible mental and physical retardation) was prevalent in severely iodine deficient populations (Kevany et al., 1969; Pharoah et al., 1971). While severe in utero hypothyroidism and cretinism are now rare in developed countries, milder degrees of maternal iodine deficiency result in subtle changes in cognition, with a difference of between 10 and 15 intelligence quotient (IQ) points compared to iodine-sufficient populations (Alexander et al., 2017; Velasco et al., 2018). Indeed, iodine deficiency is considered one of the most common preventable causes of brain damage.

Table I summarizes the human studies assessing the maternal and fetal impact of iodine deficiency and supplementation during pregnancy. The early trials showed profound benefits of iodine supplementation (Kevany et al., 1969; Pharoah et al., 1971; Cao et al., 1994) and popularized widespread iodine supplementation programs throughout the world. Later studies suggested that there could be less evident, but still significant, neurocognitive deficits associated with mild iodine deficiency (Bath et al., 2013; Hynes et al., 2013; Abel et al., 2017). There were also some studies suggesting association of preterm birth and low birth weight with mild iodine deficiency (Charoenratana et al., 2016).

The outcome of supplementation in population with mild deficiency has been variable in different studies. Whilst some studies showed definite improvement in full scale IQ and psychomotor scores of the offspring (O'Donnell et al., 2002; Moleti et al., 2016), a recent randomized control trial showed no difference between IQ of children at 5–6 years whether or not the mothers received supplements during pregnancy (Gowachirapant et al., 2017). Systematic reviews assessing impact of gestational iodine supplementation on maternal thyroid function and the neurodevelopment and growth of the offspring again showed inconsistent and modest benefits (Zhou et al., 2013; Taylor et al., 2014).

Furthermore, a few studies raised concern of potential harmful effects from an iodine excess. More than adequate iodine intake was associated with maternal subclinical hypothyroidism (Shi et al., 2015), increased thyroid autoimmunity (Pedersen et al., 2011) and preterm births (Purdue-Smithe et al., 2019). Iodine excess through prenatal vitamins were also found to have negative effects on the offspring's neurodevelopment (Rebagliato et al., 2013), thyroid development (Thomas Jde and Collett-Solberg, 2009) or thyroid function (Connelly et al., 2012).

Iodine excess and its deleterious effects can also occur during pregnancy through dietary sources (Nishiyama et al., 2004), medications affecting iodine metabolism (Lomenick et al., 2004) or preconceptional hysterosalpingography (HSG) using iodinated contrast (Mekaru et al., 2008; Kaneshige et al., 2015; Satoh et al., 2015; So et al., 2017). The studies and case reports showing impact of iodine excess in pregnancy are summarized in Table II.

Indeed, a U-shaped relationship of pregnancy outcomes with iodine levels has been described (Purdue-Smithe et al., 2019). The maternal and fetal outcome seems best at a relatively narrow range with both deficiency and excess having undesirable consequences.

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