A Systematic Review Examining the Effects of Therapeutic Radioactive Iodine on Ovarian Function and Future Pregnancy in Female Thyroid Cancer Survivors

Anna M. Sawka; Deepak C. Lakra; Jane Lea; Bandar Alshehri; Richard W. Tsang; James D. Brierley; Sharon Straus; Lehana Thabane; Amiram Gafni; Shereen Ezzat; Susan R. George; David P. Goldstein

Disclosures

Clin Endocrinol. 2008;69(03):479-490. 

In This Article

Discussion

In summary, in this systematic review, we reviewed data from 16 studies of 3023 women and adolescents with DTC, and have learned of the potential implications of RAI on subsequent gonadal and reproductive function of women. Approximately 12-31% of women may experience changes in menstrual timing or flow after RAI treatment for DTC. Transient absence of menses may occur in 8-27% of women, beginning 1-6 months or cycles after administration of therapeutic RAI and lasting between 1 and 10 months or cycles. Such episodes of transient oligomenorrhoea have been reported to be associated with transient elevations of serum gonadotrophins (FSH and LH), reflecting a state of temporary decline in ovarian function. In general, transient oligomenorrhoea and gonadotrophin elevations are expected to resolve within a year after RAI treatment for DTC. It is not currently known whether the dose activity of RAI administered, the hypothyroidism induced at RAI treatment or the use of ovarian suppression at the time of RAI treatment may modulate the risk of transient ovarian insufficiency. Of note, women with DTC who are treated with RAI in their mid-thirties or older are at higher risk of experiencing transient oligomenorrhoea after RAI compared to younger women. Women treated with RAI for DTC may experience menopause at a slightly younger age (mean or median age in the late forties) compared to women not treated with RAI (mean or median age in the early fifties). It is not known whether the dose activity of RAI or use of ovarian suppression may modulate the risk of earlier menopause. RAI treatment for DTC was not generally associated with an increased long-term risk of infertility, miscarriage, induced abortions, stillbirths, 1-year neonatal mortality, or congenital defects, particularly when compared with contemporaneous controls, such as women with DTC not treated with RAI. An increased risk of preterm labour for pregnancies of RAI-treated women was observed in only one[9] of five studies examining this outcome,[9,10,14,16,17] so this finding is of unclear significance. Data relating to an increased miscarriage in the first year after RAI treatment were conflicting, with one study reporting a miscarriage rate of up to 40%;[17] moreover, about half of pregnancies conceived within a year of RAI treatment were deliberately terminated in two studies.[9,17] High pregnancy termination rates for pregnancies conceived within 1 year after RAI treatment precluded meaningful analysis of other outcomes for this time period.

In general, international clinical practice guidelines for management of DTC have recommended that women treated with RAI wait at least 6-12 months before conceiving.[22,23,24,25,26] Although there is a paucity of evidence guiding the earliest appropriate time for conception, current clinical practice recommendations are reasonable, given the potential for an increased risk of miscarriage or induced abortion within the first year after RAI treatment and the need for optimization of levothyroxine dosing. However, beyond the first year after RAI treatment, we did not find convincing, consistent evidence suggesting that RAI treatment for DTC results in a significantly increased risk of adverse events in future pregnancies.

The strength of this review is its systematic nature, the critical appraisal of existing evidence, and the inclusion of studies in which some form of controlled comparison was reported. Some limitations of this review include the restriction to the English language, the inclusion of relatively poorer quality studies (studies incorporating historical controls, studies incompletely reporting relevant data, and studies with incomplete follow-up), relatively small sample sizes in many of the included studies, and the lack of pooled analyses. Given the variety of control groups used in studies, this methodological heterogeneity precluded meaningful pooling of outcomes. It should also be acknowledged that for relatively rare outcomes, such as congenital anomalies, the data reviewed here may be relatively underpowered to detect a slight but statistically significant increase in risk, if it exists. A limitation of many of the primary data collected was the lack of age matching or age adjustment in many of the controlled comparisons. Furthermore, many of the primary data were lacking in detailed information on maternal comorbidities and lifestyle factors (such as smoking) and the degree of TSH suppression achieved with levothyroxine treatment. It is possible that fluctuations in TSH following initiation of levothyroxine therapy may have contributed to some of the reported menstrual irregularities and pregnancy outcomes within the first year after RAI treatment, particularly in studies in which contemporaneous controls treated with levothyroxine were not used. The conclusions related to general outcomes in pregnancies and offspring should thus be interpreted as largely reflecting a lack of evidence of harm based on the best available evidence, and not necessarily proof of safety.

We would encourage future larger controlled prospective studies examining gonadal and reproductive effects of RAI in women with DTC and clinical outcomes in their offspring. For example, research should be conducted comparing the short- and long-term gonadal outcomes in women receiving RAI who are pretreated with recombinant TSH (rhTSH) compared to those who are rendered hypothyroid, as the radiation dose to the blood may be lower with rhTSH pretreatment.[27] Furthermore, any potential protective effect of administration of ovarian suppression at the time of RAI treatment may be of interest to explore, particularly with respect to age of future menopause. In the meantime, it is important to counsel women who are considering RAI treatment for DTC that, based on controlled comparisons from existing observational data, there is little evidence to suggest important adverse effects of RAI on gonadal function, fertility or pregnancy outcomes beyond 12 months after RAI; a possible exception to this statement is the finding of a slightly earlier menopause observed in RAI-treated women.


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