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


Hum Reprod. 2021;36(2):265-274. 

In This Article

Ideal Therapeutic Iodine Supplementation in UI

Lipiodol HSG has been shown to improve fertility in women with endometriosis and UI (Johnson et al., 2004; Mohiyiddeen et al., 2015; Dreyer et al., 2017; van Rijswijk et al., 2018).

However, a study in a small group of 22 women by Kaneshige et al. (2015) raised safety concerns, with 100-fold elevation of iodine levels in women undergoing Lipiodol HSG procedure. With Lipiodol having a long half-life (50 days) and assuming a conservative 2 ml of Lipiodol is retained following an HSG, about 480 mg of iodine is released in the initial 50 days. This is approximately 10 000 μg/day, which is more than 50 times the recommended daily allowance. Even after 5 half-lives or 250 days, about 600 μg/day of iodine is released, which is still 3-fold the normal requirement. Excess iodine load can cause transient hypothyroidism by the Wolff–Chaikoff effect (Leung and Braverman, 2014). In certain situations, such as autoimmune thyroiditis and in the fetus and neonate, the effect may be more severe and persistent resulting in prolonged hypothyroidism.

Indeed, an increased incidence of transient subclinical hypothyroidism in women undergoing Lipiodol HSG has been shown (Mekaru et al., 2008; Kaneshige et al., 2015; So et al., 2017). Suppression of thyroid function was more enhanced in those with baseline subclinical hypothyroidism, with more than a third developing overt hypothyroidism (Mekaru et al., 2008). In addition, thyroid suppression following Lipiodol (480 mg iodine) lasted longer compared to that caused by water-soluble contrast (Isovist, 300 mg iodine) (So et al., 2017). Importantly, these studies were in Japanese populations who generally had sufficient or excess iodine at baseline due to seaweed consumption and extrapolation to other populations may not be possible. In addition, these studies did not directly compare the iodine levels to the thyroid function and had methodological issues including variable timing of thyroid function assessment.

Excess iodine during pregnancy can also potentially affect the fetal thyroid gland development and neonatal thyroid function. There have been multiple case reports of amiodarone therapy during pregnancy causing newborn hypothyroidism (Laurent et al., 1987; Bretremieux et al., 1988; Aguilar et al., 1992; Bartalena et al., 2001). The thyroid dysfunction was transient with the neonates requiring only short term thyroid hormone replacement, suggesting the underlying etiology was fetal iodine exposure and a prolonged Wolff–Chaikoff effect causing suppression of fetal thyroid hormone release (Lomenick et al., 2004). Transient TSH abnormalities and permanent hypothyroidism were similarly observed in babies conceived in the immediate cycles following Lipiodol HSG in a study on 212 neonates conceived within 6 months of Lipiodol HSG in Japan (Satoh et al., 2015). This, however, was not replicated in a later study on a Caucasian population (van Welie et al., 2020) which found no increase in hypothyroidism for babies conceived following Lipiodol HSG. The later study was a post hoc analysis in a Dutch population and used a screening program with T4 followed by TSH, possibly missing cases of transient thyrotropinemia.

This brings us to the possibilities of alternative methods of Lipiodol or iodine administration with similar fertility advantage, but better safety profile. Whether iodine given either by a subcutaneous or intramuscular route improves fertility to the same extent as Lipiodol HSGs remains unclear. Lipiodol given as single oral dose of three capsules (570 mg of iodine) vs a single intramuscular dose (1 ml of Lipiodol–480 mg of iodine) produced similar iodine profile in a case–control study with no clinical or laboratory adverse effects (Leverge et al., 2003). Subcutaneous single dose of Lipiodol in iodine-deficient sheep resulted in 100% pregnancy rates vs 37% among the controls (Ferri et al., 2003). Oral and intramuscular iodized oil had similar effectiveness in prevention of thyroid disorders in Zaire (Phillips et al., 1988).

In conclusion, more studies are warranted to understand the role of iodine and Lipiodol in UI. Lipiodol hysterosalpingography has proven beneficial in UI, however the safety aspects of chronic iodine excess need further study. It is possible that higher iodine levels improve conception and this will need to be balanced against the potential for maternal and offspring morbidity. The safe and efficacious dose in UI, iodine preparation and route of administration are also areas that require further research.