Thyroid and female fertility: a survey on the clinical practice among endocrinologists belonging to the italian thyroid association.

The short and anonymous questionnaire included 14 multiple choice questions. All questions were reviewed by scientific coordinators of AIT and was sent to 2171 email addresses, belonging to AIT members and physicians registered on the AIT platform for online training. Only responders who completed the survey in all its parts were included in the study. The survey investigated three main areas: 1) organization and outpatients management of women with thyroid disease of chilbearing age 2) therapeutic intervention before and during pregnancy 3) clinical management of infertile patients submitted to ART.

From the 1193 users of the mailing readers (56.3% of the total), 228 answered our survey (19.1% of readers). There were respondents from most of the Italian regions. However, being the questionnaire anonymous, we have no informations about the characteristics of respondents (eg. age, sex, place of work or years of experience in thyroid field). Starting from the organization of the outpatient clinics, there is a specific service dedicated to fertility and pregnancy in about 50% of the responders referring centers, while, according to the first key question of the survey (“During endocrinological evaluation of a woman of childbearing age do you ask for the desire for pregnancy?”) almost the totality of participants (97.4%) answered affirmatively. Concerning the pre-conception phase, 69.7% of respondents suggest iodine supplementation in women searching for pregnancy, while 30.3% of them do not give any indication about it. On the other hand, when visiting women in childbearing age, almost all participants give information about the evaluation of thyroid function tests (TSH and FT4) in case of positive pregnancy test. Current guidelines suggest that hypothyroid patients achieving or with a suspected pregnancy should independently increase their dose of L-thyroxine by about 30% to guarantee the dual, maternal and fetal needs [ 6 ]. This so-called “blind increase” is always applied by 43% of participants, while 14.5% of them limit it to patients submitted to Assisted Reproduction Techniques (ART) and 42% do not use it. Moreover, in our country, according to the question #10, it’s very common that pregnant patient come to our observation with a L-thyroxine therapy previously started by the gynecologist. Although it’s not clearly defined if thyroid autoimmunity represents an epiphenomenon of a systemic autoimmune disorder, we further asked our respondents if they screen the presence of thyroid autoimmunity in patients affected by other concomitant autoimmune diseases (e.g. celiac disease, Addison disease, inflammatory bowel disease, etc.) and results showed that 93.9% of them are used to delve into this aspect. Similarly, since a significant association between thyroid disorders and ovarian diseases exists [ 8 ], we asked if Italian thyroidologists investigate the thyroid function in women with one of the most frequent ovarian diseases in childbearing age, such as Polycystic Ovary Syndrome (PCOS), and again, the responses were almost unanimous, with the 90.8% of interviewed answering “yes”. As said before, current guidelines for the management of thyroid diseases and pregnancy still include controversial/critical (not uniform) indications, particularly in the case of subclinical hypothyroidism with TSH between 2.5 mU/L and Upper Limit of the Reference Range (ULRR) [ 6 ]. To understand the Italian approach, we asked to participants their position on eventual L-thyroxine starting treatment in the case of woman in the first trimester of pregnancy with TSH between 2.5 and 4.0 mU/L and positive thyroid antibodies. The 87.3% of the interviewed would start therapy, while the 12.7% wouldn’t suggested it (Fig.  1 A). In addition, we asked a second question on the therapeutical intervention in a woman in the first trimester of pregnancy, without positive thyroid antibodies and TSH between 2.5 and 4.0 mU/L, but with a history of previous history of miscarriage. Unlike the previous unanimous response, in this case, the Italian thyroidologists were divided with 56.6% of them supporting a positive role of L-T4 treatment (Fig.  1 B). Fig. 1 Starting a low dose of LT4 in women in the first trimester of pregnancy with serum TSH between 2.5- 4 mU/L ( light grey : yes, dark grey : no). ( A ) In case of TAI +. ( B ) In case of TAI-with previous miscarriage Starting a low dose of LT4 in women in the first trimester of pregnancy with serum TSH between 2.5- 4 mU/L ( light grey : yes, dark grey : no). ( A ) In case of TAI +. ( B ) In case of TAI-with previous miscarriage Lastly, concerning the infertile patients submitted to ART, when asked if TSH (measured before starting ART procedure) had to be re-evaluated after ovarian stimulation, only 68% of participants answered affirmatively, while 32% of them do not measure it again (Fig.  2 A). The majority of positive responders perform the re-test of TSH in order to verify the increase of serum TSH after the estrogen peak. The remaining specialists re-evaluate TSH only in women with positive thyroid antibodies (17.3%) or in hypothyroid patients already on L-T4 therapy before ovarian stimulation (11.1%) (Fig.  2 B). Looking at the timing of the repetition of serum TSH measurement, more than 70% of responders suggest checking the TSH at the time of hCG measurement, while almost all the others at the oocyte pick-up (25%) (Fig.  2 C). Fig. 2 Re-evaluation of serum TSH levels after controlled ovarian stimulation (COS). ( A ) Do you re-test serum TSH after COS? ( light grey : yes, dark grey : no). In which patients would you perform the TSH re-evaluation after COS? Dark grey : in all patients. Light grey : only in TAI + patients. Mid-Grey : only in hypothyroid patients on LT4. ( B ) When would you do the re-testing?  Dark grey : at the hCG measurement.  Light grey : at the oocyte pick-up. Mid-Grey : other Re-evaluation of serum TSH levels after controlled ovarian stimulation (COS). ( A ) Do you re-test serum TSH after COS? ( light grey : yes, dark grey : no). In which patients would you perform the TSH re-evaluation after COS? Dark grey : in all patients. Light grey : only in TAI + patients. Mid-Grey : only in hypothyroid patients on LT4. ( B ) When would you do the re-testing?  Dark grey : at the hCG measurement.  Light grey : at the oocyte pick-up. Mid-Grey : other

The relationship between thryoid function and female fertility is a field of increased interest. Thyroid hormones (TH) are known to play a critical role in various reproductive events, including ovulation as well as the embryo implantation and pregnancy [ 1 ]. Thyroid disorders, particularly thyroid autoimmunity (TAI) are prevalent in the fertile age, being estimated at around 10% in general population and higher in women seeking counselling for infertility [ 1 – 3 ]. TAI, which can be also considered as an epiphenomenon of generalized immune dysfunction is characterized by a strong inflammatory infiltration of the thyroid involving including cytokines and chemokines which play an important role in ovarian aging suggesting a negative contribute on ovarian dysfunction [ 4 ]. Moreover, it can lead to an impaired thyroid ability to produce the adequate thyroid hormones leading to hypo or hyperthyroidism. Both conditions can have detrimental effect on either the pre-conceptional phase causing menstrual cycle disturbances or on many maternal and neonatal complications, including early miscarriage, recurrent pregnancy loss, placenta abruption, preterm delivery, maternal congestive heart failure and preeclampsia, postpartum hemorrhage, low birth weight, neonatal respiratory distress [ 5 ]. Due to the progressive increase of infertility and diffusion of assisted reproduction technology (ART), the optimal reference range of TSH for women of childbearing age, as well as during ovarian stimulation, has become a matter of debate. In this last decade specific guidelines on management of thyroid disease during pregnancy and post-partum and on thyroid disorders prior and during ART have been published [ 6 , 7 ]. However, there are still some grey areas in which the clinicians must choose the intervention on a personalized basis, case by case. To assess the current state of Italian clinical practice on female patients in fertile age, we analyzed responses to a short questionnaire reaching all thyroidologists of the Italian Thyroid Association (AIT).

In the last years, due to the increase of patients submitted to ART and to the high prevalence of thyroid disorders in the fertile age, recent guidelines have been published either as far as the management of thyroid diseases in pregnancy is concerned [ 6 ] or the clinical endocrinological approach in women submitted to ART [ 7 ]. This short survey aimed to evaluate the current management of these patients in Italy in order to understand if the clinical approach to women in childbearing age is standardized among Italian thyroidologists. Although only 50% of Italian centers has a clinic dedicated to these particular patients, almost all Italian thyroidologists follow pregnant patients and most of them contribute to the optimization of the thyroid status prior and during ART. Nevertheless, this survey identified some discordant applications of American Thyroid Association (ATA) and European Thyroid Association (ETA) guidelines. In particular, 30% of clinicians do not suggest the supplementation with iodine. It is known that iodine supplementation during pregnancy is still matter of debate. However, current ATA guidelines recommend to start, optimally 3 months prior to pregnancy, an iodine supplementation [ 6 ], similarly to what suggested for folic acid, in women living in regions with mild iodine deficiency. During the period 2015–2019 Italy has achieved the status of iodine sufficiency thanks to the nationwide voluntary iodine prophylaxis program introduced in 2005 [ 9 ]. Moreover, a more recent overview of the evidence which includes seven meta-analyses aimed to clarify controversial aspects regarding the role of iodine in pregnancy, proposed to recommend to all pregnant women a regular use of iodized salt and a supplementation with 150 mcg daily of potassium iodide, started at least 3 months before conception [ 10 ]. Concerning the replacement treatment, the so-called “blind increase” of 30% of the L-thyroxine dose in hypothyroid patients achieving or with a suspected pregnancy is a clinical approach employed by less than 60% of italian thyroidologists, 15% of whom only in case of ART patients but, probably, this is due to the recent availability to promptly adjust L-T4 dose using telemedicine. The majority of Italian thryoidologist are confident in a useful effect of L-thyroxine in women with TSH between 2.5 and ULRR (4 mU/L) in the presence of thyroid autoimmunity, while they do not trust that L-T4 can prevent a miscarriage in women with previous pregnancy loss if the antibodies are negative. Reflecting the grey areas of the current guidelines, which delegate to the clinician the individualized therapeutic decision [ 6 ], this is one of the most controversial aspects on thyroid diseases in relation to fertility/pregnancy. In fact, it is well known that thyroid autoimmunity affects nearly 10% of women of reproductive age, particularly with unexplained infertility, PCOS or endometriosis; moreover, it may be connected with and increased risk of miscarriage. Nevertheless, the pathological mechanisms underlying these observations remain unclear, similarly to the role of L-T4 therapy which seems to be ineffective in preventing negative pregnancy outcomes in euthyroid women with thyroid autoimmunity. The results of the present survey suggest that Italian thyroidologists mainly aim to avoid the occurrence of hypothyroidism in the early phase of pregnancy. Finally, the most “discordant” results between the current guidelines and the current Italian clinical management are in relation to the clinical approach of women undergoing ART. Of course, this is a relative new field of interest and in the last 10–15 years an increasing number of observations and publications, by either endocrinologists or gynecologists, led to follow very strict but not so proven indications (eg the threshold of TSH before the Controlled Ovarian Stimulation, COS). The present survey report that almost 70% of clinicians re-test all infertile women after COS in order to re-evaluate serum TSH after the estrogen peak although the ETA guidelines published in 2021 recommended checking TSH levels after COS at second/confirmatory hCG measurement only in women with thyroid autoimmunity during LT4 treatment or after initiation of the therapy [ 7 ]. Probably in the next future, following the increasing pathophysiological insights and considering the multiple procedures, eg. homologous vs heterologous ART, leading to different response of TSH levels based on elevated (COS) or slight (endometrial stimulation) increase of estrogen, there will be different clinical approaches more and more tailored to the patients. In conclusion, this Italian survey uncovered the principal grey areas remaining in the clinical management of women of childbearing age. Specifically, we highlighted the critical role of iodine supplementation in preconception planning and, considering the growing prevalence of women undergoing ART, the necessity of specialized training for endocrinologists in this area, also through a profitable interaction with other experts and scientific societies in the field of reproduction which could mutual improve the knowledge of the binomial thyroid and female fertility. Consequently, according to the results of this survey, the objective will be promoting education to endocrinologists nationwide by providing clear and accessible communication of the practical recommendations outlined in the clinical guidelines, in order to avoid useless investigations and allow to invest education energy and costs where necessary. Table 1 The questions of the survey subdivided into the three main areas of interest Questions Answers (%) Yes No Organization and outpatients management of women with thyroid disease of chilbearing age #1. During endocrinological evaluation of a woman of childbearing age do you ask for the desire for pregnancy? 97.4 2.6 #3. Do you give any indications on the management of a possible pregnancy at the end of a visit to a patient of childbearing age? (TSH and FT4 in case of confirmed pregnancy) 96.9 3.1 #5. In your center is there a clinic dedicated to the management of patients with thyroid diseases planning conception or during pregnancy? 50.9 49.1 #6. Do you recommend screening for thyroid disease in a woman with non-thyroid autoimmune disease? 93.9 6.1 #7. Do you evaluate TSH when evaluating women with polycystic ovary syndrome? 90.8 9.2 #10. Have you ever visited a pregnant patient with L-thyroxine replacement therapy started by a gynecologist? 83.8 16.2 Therapeutic intervention before and during pregnancy #2. Do you suggest iodine supplementation before pregnancy? 69.7 30.3 #8. Do you start L-thyroxine therapy in a pregnant patient in the first trimester with positive anti-thyroid antibodies and TSH between 2,5-4 mU/L? 87.3 12.7 #9. Do you start L-thyroxine therapy in a pregnant patient in the first trimester with a previous miscarriage with negative anti-thyroid antibodies and TSH between 2,5-4 mU/L? 56.6 43.4 Clinical management of infertile patients submitted to ART Yes No In patients submitted to ART #11. Do you follow women with thyroid disease during ART? 72.4 27.6 #4. Is a 30% blind increase recommended in your center in the case of a positive pregnancy test? and in case of ART? 43.4 42.1 14.5 #12. Do you evaluate TSH after ovarian stimulation in a patient undergoing ART? 68 32 In all women In women with positive antibodies In hypothyroid patients already on L-T4 therapy before ovarian stimulation #13. If yes at the question # 12 In all patients or just in Ab+? 71.6 17.3 11.1 At the time of hCG measurement At the oocyte pick-up Other #14. If yes at the question # 12 When? 73.9 22.9 3.2 The questions of the survey subdivided into the three main areas of interest