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

Unexplained Infertility—An Enigma

Unexplained infertility (UI) is defined as the lack of conception in a couple after one year of regular unprotected sex and the absence of an identifiable cause for infertility in either of the partners (Gelbaya et al., 2014). The prevalence of UI varies, with different studies, quoting prevalence rates between 5% and 30% (Adamson and Baker, 2003; Isaksson and Tiitinen, 2004). The diagnosis of UI remains controversial because some argue these are missed cases of endometriosis, premature ovarian aging, tubal problems or immunological infertility (Siristatidis and Bhattacharya, 2007). Thus, UI probably reflects a range of pathologies, including conditions that have not been diagnosed but may well be contributing to the infertility.

UI is not an absolute condition, but rather a relative inability to conceive. Many of these couples conceive without treatment and expectant management is often recommended for younger women (Isaksson and Tiitinen, 2004). The rate of spontaneous conception after 1 year of UI is encouraging with 50% conceiving within the next 12 months and a further 12% in the following year (Gelbaya et al., 2014). IUI and IVF are sometimes offered based on clinical judgment, with variable success rate of 15–30% and 30–60%, respectively (Reindollar et al., 2010; Farquhar et al., 2018). The benefit of assisted reproductive technologies over the 'wait and watch' approach is debatable and the success rates are determined by various factors such as the duration of UI, age of patient, number of IUI cycles and use of additional fertility medications such as clomiphene or FSH (Adamson and Baker, 2003; Brandes et al., 2010; Reindollar et al., 2010; Farquhar et al., 2018).

The increased risk of multiple pregnancies and concern of long-term metabolic complications in the offspring highlight the importance of judicious use of IVF and opting for more conservative approaches (Mol et al., 2018). These other treatment modalities are cheaper and promote spontaneous conception or better conception rate following IUI, by favoring implantation. Since the 1950s there have been reports of increased fertility following HSG with Lipiodol, an oil-soluble contrast media. Further studies in the last two decades reinforced these early findings (Johnson et al., 2004, 2007; Johnson, 2014). A recent large randomized study has confirmed these studies and Lipiodol was found to increase fertility rates in UI compared to a water-soluble contrast media (WSCM) (39.7% vs 29.1% over 6 months) (Dreyer et al., 2017; van Rijswijk et al., 2018). Other than being a poppy seed oil-based product, Lipiodol has a number of other characteristics including being relatively viscous, non-ionic and containing more iodine than most other contrast media (480 mg/ml). Individual WSCM used for HSG have physical properties that vary substantively to one another with respect to ionicity, viscosity, hyperosmolarity and iodine content. The iodine content, however, has always been less than Lipiodol with concentrations between 250 and 380 mg/ml (Rasmussen et al., 1991; Fang et al., 2018). Lipiodol also has a much longer half-life if retained in the body (50 days vs 2–3 h for WSCM) which can lead to prolonged iodine exposure (Brown et al., 1949; Miyamoto et al., 1995). The underlying mechanism(s) by which Lipiodol improves conception rates remain unclear but are likely multifactorial. These include a flushing effect of removing debris and obstructions from the fallopian tubes (van Welie et al., 2019), an immunobiological peritoneal bathing effect (Izumi et al., 2017) and an immunobiological uterine bathing effect of the Lipiodol on the endometrium favoring implantation (Johnson et al., 2019). However, the uniquely high iodine concentration and long half-life of Lipiodol warrants consideration of iodine as a potential factor improving fertility.