Sub-Clinical Hypothyroidism & Miscarriage: Untangling the Data

Guest post by Rashmi Kudesia, MD MSc

Earlier this year, in tweeting out a medical article about hypothyroidism and fertility, I concluded that “the debate rages on”. Unfortunately, the same is true about the connection between hypothyroidism and miscarriage – the scientific data is conflicting, expert opinions and guidelines clash, and so we each must try to sift through the literature and come to a conclusion we feel serves our patients best. Given the seemingly higher rates of thyroid dysfunction among women with PCOS, many of our regular readers are probably very curious to know – what is the most evidence-based management of the thyroid for women trying to conceive?

I’ll start with what we definitely know. The thyroid is a small gland that sits in your neck, and in response to its stimulating signal (thyroid-stimulating hormone, or TSH, released from the pituitary gland in the brain), it secretes thyroid hormone. The thyroid is primarily metabolic in function, and when hormone levels are low, we feel cold, tired, sluggish and can have dry skin, weight gain and irregular menstrual cycles. In this situation, the risks for mothers and babies increase; we see higher rates of miscarriage, preeclampsia, placental abruption, anemia and postpartum hemorrhage, preterm birth, low birthweight babies, and children with impacted neuropsychological development. Many of these associations have been well-described for over a century and continue to be demonstrated in epidemiologic studies. For example, a Danish study retrospectively exploring the family sizes of women with thyroid dysfunction noted that women with hypothyroidism had fewer children, and later in life.

In many parts of the world, iodine (which serves a critical role in thyroid function) deficiency is the main culprit causing hypothyroidism. In iodine-sufficient areas, like the U.S., the most common cause is an autoimmune condition, Hashimoto’s thyroiditis, which is present in less than 1 in 100 women. However, the controversy is about less severe forms of possibly thyroid dysfunction, namely subclinical hypothyroidism (SCH), which is where the TSH level starts to rise (suggesting the brain is “working harder” to get the thyroid to work), but thyroid hormone is still at normal levels. Unfortunately, as many studies use different diagnostic cutoffs, or check bloodwork in pregnancy, it becomes tricky to figure out how to best manage those trying to conceive. But let’s walk through a summary.

One sub-question is at what cutoff SCH should be diagnosed. Most laboratory assays have an upper limit of normal somewhere between 4-5 mIU/L. However, the National Academy of Clinical Biochemistry has suggested that 95% of individuals without evidence of thyroid disease have a TSH level <2.5 mIU/L, and for many studies, this number has been used as a potential cutoff. In a variety of studies of differing qualities and in different parts of the world, some have shown an impact of the “high normal” (TSH of 2.5-4.5 mIU/L) levels, many of which are summarized in a 2017 systematic review. The largest multi-center study in the US, however, showed that among healthy women who did not have infertility but had 1-2 prior miscarriages, SCH did not affect rates of getting pregnant, miscarriage or live birth.

As a result, the American Society for Reproductive Medicine (ASRM) standpoint is that if the TSH is >4 mIU/L, treatment with levothyroxine should be initiated to get the TSH below 2.5 mIU/L. If the initial level is 2.5-4, however, one could either start treatment or monitor levels. Most reproductive endocrinologists do end up starting treatment, because levothyroxine is overall a well-tolerated, inexpensive medication, and we don’t want to take chances with highly-desired pregnancies and treatment cycles in our patients! In my mind, since the goal TSH in the first trimester is 2.5 mIU/L, it makes sense to try and get there prior to pregnancy.

The second big topic is the role of thyroid auto-immunity (TAI), particularly the anti-thyroid peroxidase (anti-TPO) antibodies. In one systematic review, with 3 out of 4 included studies conducted in Italy (a country that still has more substantial iodine deficiency than in the United States), women whose thyroid levels were normal but had TPO antibodies had a higher rate of preterm birth and miscarriage. Similar results have been shown in iodine-sufficient areas of China, as well as other locales. Of course, reports showing no impact of TAI have also been published (such as in that large U.S. multi-center study)! So, the ASRM guidelines suggest that there is only “fair evidence” of an association of TAI with both miscarriage and infertility. The suggested approach is to check for TAI if TSH levels are persistently >2.5 mIU/L or if there are clinical risk factors for thyroid disease, and if found, to keep TSH levels below 2.5 mIU/L.

You might wonder at this point, if it’s all so unclear, why it just doesn’t make sense to check and treat everyone! After all, it is true that hypothyroid symptoms are very non-specific, and only testing those women that report a clear clinical, personal or family history will result in some women having missed diagnoses. However, the difficulty with this literature is that finding higher rates of a condition (SCH, TAI, etc.) in women with a miscarriage or infertility history does not prove causation – many women having healthy full-term births may have it too! It would be like saying well, a lot of women who have miscarriages have brown hair, so that might be a risk factor (of course, it’s not!).

When it comes to recommending a screening, there should be strong evidence to tie a condition to a specific disease or bad outcome, and an intervention that would help mitigate that association. Indeed, based on the lack of proven benefit of screening all pregnant women, the American College of Obstetricians & Gynecologists and American Thyroid Association (ATA) have recommended against universal TSH screening in pregnancy. However, ASRM, ATA and the Endocrine Society have all agreed that testing infertile women trying to conceive is appropriate.

It is important to know, however, that though no one wants to take unnecessary chances, we are also likely putting a lot of women on medication without a clear benefit. A Puerto Rican study indicated that using the TSH cutoff of 2.5 mIU/L would result in a SCH prevalence of 37%, as opposed to only 9.6% at the 4 mIU/L cutoff. That low threshold causes many more women to require treatment! As to the actual impact of treatment, a large U.S.-based study showed women with SCH and TSH ranging 2.5-4 mIU/L experienced no benefit from treatment – and although those with TSH 4.1-10 mIU/L had a lower miscarriage rate, they also had higher rates of preterm birth, gestational diabetes and preeclampsia (suggesting that there could be downsides to thyroid treatment). Among women starting IVF cycles, treatment of TSH in the 2.5-4.2 mIU/L range showed no benefit. Another systematic review and meta-analysis concluded, based on the weak available evidence, that among pregnant women with SCH, those that received levothyroxine (versus those untreated) had no significant difference in pregnancy loss, preterm birth, gestational hypertension, low birthweight or low Apgar scores. A paper following patient cohorts in a specialized recurrent miscarriage program showed no difference in subsequent live birth rates between those women who had SCH and those who didn’t, or even between those with SCH that were untreated versus treated.

Wow! If you made it this far, you might have a headache by now, trying to wrap your mind around all these caveats and conflicting details! It’s a complex clinical question, but this much is clear:

• If you have a history of infertility or miscarriage or are undergoing fertility evaluation or treatment, get your TSH checked and try to keep it under 2.5 mIU/L
• Many women with PCOS will use fertility treatment and therefore fall under the above category, but if you ovulate on your own and are trying to conceive, given the higher chances of thyroid dysfunction and the difficulties in clinical diagnosis due to the overlap in hypothyroid and PCOS symptoms, I would recommend a pre-pregnancy TSH
• There is no proven benefit of one type of thyroid hormone replacement versus another
• In pregnancy, the goal TSH levels for each trimester are 2.5, 3 and 3.5 mIU/L, respectively, and you will need to adjust your pre-pregnancy dose right when you get pregnant because your thyroid requirement goes up temporarily in early pregnancy
• As there is no evidence-based treatment for TAI with TSH<2.5 mIU/L, I follow the guidelines and don’t hunt for it (though other physicians I respect may do so).

Hopefully, future research will clarify the true relationship between thyroid health and miscarriage, and identify effective treatment strategies. In the meantime, I hope this long but detailed summary helps you feel a little more confident thinking about the best approach for your thyroid and reproductive health!

Dr. Kudesia is a board-certified Reproductive Endocrinology and Infertility specialist, practicing at Houston IVF in Houston, Texas. She joined Houston IVF in 2018 after practicing in New York City, where she was named a “New York Super Doctors Rising Star” in 2016 and 2017.

After completing her Baccalaureate degree in Biology & Medicine magna cum laude from Brown University, she received her M.D. with honors from the Duke University School of Medicine, where she was selected into a clinical research training program co-sponsored by the National Institutes of Health. Her residency training in Obstetrics & Gynecology at the New York Hospital-Weill Cornell Medical Center was followed by subspecialty training in Reproductive Endocrinology and Infertility (REI) at the Albert Einstein College of Medicine-Montefiore Medical Center, alongside a Masters’ of Science degree in Clinical Research Methods. She subsequently served as a Clinical Assistant Professor at the Icahn School of Medicine at Mount Sinai, as well as the Research Rotational Director for the REI fellowship, and Medical Director of the Brooklyn office of the Reproductive Medicine Associates of New York.

Dr. Kudesia is a Fellow of the American College of Obstetricians and Gynecologists, and an active member of the American Society for Reproductive Medicine (ASRM), Society for Reproductive Endocrinology and Infertility, Androgen Excess & Polycystic Ovary Syndrome Society, and American Medical Association (AMA). She has served in multiple local and national leadership roles in organized medicine, including her current positions as Secretary of the ASRM Women’s Council Executive Board and the ASRM delegate to the AMA Young Physicians’ Section.

Dr. Kudesia has also presented scientific research at national and international conferences, and has received multiple awards and grants for her work. She has published peer-reviewed articles and book chapters, including in leading journals such as Fertility & Sterility and the American Journal of Obstetrics & Gynecology, as well as editing a theme issue on reproductive medicine for the American Medical Association Journal of Ethics. Her current areas of focus include improving in vitro fertilization cycle prognosis, polycystic ovary syndrome, LGBT fertility, and fertility awareness, counseling, and access to care. She actively promotes women’s health and wellness on social media via Twitter, Facebook, and Instagram.