Preconception Thyroid Function Can Predict Delayed Time to Pregnancy, Risk of Spontaneous Abortion

Haixia Guan, MD, PhD

A new study assessing data from more than 11 million women is shedding light on the impact of preconception thyroid function on fecundability and risk of pregnancy loss prior to 20 weeks’ gestation.

A population-based cohort study evaluating associations of preconception thyrotropin levels with time to pregnancy and risk of spontaneous, results of the study suggest both high and low preconception thyrotropin levels were associated with delayed time to pregnancy, with high levels also associated with up to a 33% increase in likelihood of spontaneous abortion.

“To our knowledge, this is the first population-based cohort study to report that preconception thyrotropin levels outside reference range may be associated with reduced fecundability and increased risk of spontaneous abortion. Our findings support that a preconception thyrotropin between the lower reference limit and 2.5 mIU/L was associated with the lowest risk of these adverse reproductive outcomes,” wrote investigators. “These findings provide important evidence for preconception health care and suggest that interventional studies investigating the benefits of preconception thyroid function screening and levothyroxine supplementation are warranted.”

Although there is a plethora of studies and data linking thyroid dysfunction during pregnancy to increased risk of adverse pregnancy outcomes, a dearth of information exists related to associations of preconception thyrotropin levels with reproductive outcomes. With this in mind, a team from Guangdong Academy of Medical Sciences and National Health Commission of the People’s Republic of China designed their study with the intent of estimating the associations between preconception thyrotropin levels with time to pregnancy and risk of spontaneous abortion in a population-based cohort.

Using the Chinese National Free Prepregnancy Checkups Project, investigators identified more than 12.8 million female individuals aged 20-49 years who were trying to conceive were enrolled between January 1, 2013, and December 31, 2016, for inclusion in their analyses. The project was launched in 2010 as a national preconception health care service aimed at providing free preconception health examinations, counseling, and follow-up of pregnancy outcomes for reproductive-aged couples who plan to conceive. From the 12,834,600 included in the project, 11,538,049 had prepregnancy thyrotropin level testing and were planning for pregnancy. Of these, 344,047 were excluded and 11,194,002 were identified for inclusion in the investigators’ primary analysis of fertility. The most common reason for exclusion was diagnoses of infertility among women or male partners. This cohort had a mean age of 27.56 (SD, 5.10) years, with 42.34% of participants becoming pregnant within 1 year.

Investigators noted 6,515,323 of the 11,194,002 included in the primary analysis of fertility were excluded from the primary analysis of spontaneous abortion, which resulted in a final cohort of 4,678,679. Of those excluded, the majority were excluded because they did not conceive prior to December 31, 2017, and the remaining 60,742 were excluded due to other adverse pregnancy outcomes, including ectopic pregnancy and therapeutic or medically induced abortion. Among the 4,678,679 individuals included in this cohort, 108,064 spontaneous abortion events were observed during the follow-up.

For the purpose of analysis, time to pregnancy was assessed using hazard ratios and spontaneous abortion was assessed using odds ratios, with plans to use restricted cubic spline regression to assess thyrotropin dose-response associations. Investigators pointed out Cox proportional hazards regression models estimating HRs for time to pregnancy were adjusted for characteristics of female participants and potential factors associated with fecundability, including preconception BMI, education, area of residence, alcohol drinking, smoking, passive smoking, hypertension, type 2 diabetes, history of thyroid disease, reproductive tract infections, hepatitis B virus surface antigen–positivity status, age at menarche, menstrual cycle length, and menstrual period length. Investigators also pointed out logistic regression models estimating the associations with spontaneous abortion were adjusted for age at last menstrual period, BMI, education, area of residence, alcohol drinking, smoking, passive smoking, hypertension, diabetes, history of thyroid disease, and adverse pregnancy outcomes.

Upon analysis, results indicated both low and high preconception thyrotropin levels were associated with delayed time to pregnancy compared to thyrotropin levels in the reference range of 0.37-2.49 mIU/L (thyrotropin <0.10 mIU/L: HR, 0.90 [95% CI, 0.89-0.92]; thyrotropin 4.88-9.99 mIU/L: HR, 0.86 [95% CI, 0.86-0.87]; thyrotropin 10.00 mIU/L: HR, 0.78 [95% CI, 0.77-0.79]; P for all <.001). When assessing associations with spontaneous abortion, results indicated increased thyrotropin levels were associated with an increased risk of spontaneous abortions (thyrotropin 4.88-9.99 mIU/L: OR, 1.33 [95% CI, 1.28-1.38]; thyrotropin 10.00 mIU/L: OR, 1.25 [95% CI, 1.14-1.36]; P for all <.001).

In an invited commentary, Erik Alexander, MD, chief of the thyroid section in the Division of Endocrinology, Diabetes, and Hypertension at Brigham & Women’s Hospital and Harvard Medical School, applauded investigators for their study and its additions to the existing knowledge base, but cautioned against overinterpretation of study results given its inherent limitations.

“Active awareness of a patient’s thyroid illness and their symptoms remains a best practice. Avoiding severe hyperthyroidism and moderate to severe hypothyroidism could improve chances for successful conception and a healthy pregnancy. But exactly what thyrotropin concentration should be targeted at what time point before conception and when treatment of mild hormonal imbalance should be initiated remain only partially defined,” Alexander wrote. “Nonetheless, investigations, such as the study by Yang et al, help move us toward better understanding of an illness that is exceedingly common and readily treatable. We may not yet know precisely how best to treat hypothyroidism and hyperthyroidism, but we are getting closer.”

This study, “Association of Preconception Thyrotropin Levels With Fecundability and Risk of Spontaneous Abortion in China,” was published in JAMA Network Open.