Highlights
- The Danish PRETHYR multicenter study provides the first comprehensive report on clinical management patterns for hyperthyroidism in pregnant women in Denmark.
- Approximately 58.8% of women with known preconception thyroid disease required antithyroid drug (ATD) therapy during pregnancy.
- A significant proportion of patients (59.1%) were switched from methimazole (MMI) to propylthiouracil (PTU) prior to conception to minimize teratogenic risks.
- Higher pre-conception TRAb and lower TSH levels were identified as primary clinical indicators for the continuation or initiation of ATD therapy during the first trimester.
Background: The Challenge of Gestational Hyperthyroidism
Hyperthyroidism in pregnancy, predominantly caused by Graves’ disease (GD), presents a complex clinical challenge requiring a delicate balance between maternal health and fetal safety. Untreated or poorly controlled hyperthyroidism is associated with severe adverse outcomes, including pre-eclampsia, maternal heart failure, thyroid storm, spontaneous abortion, and fetal growth restriction. Conversely, the pharmacological agents used to treat the condition—antithyroid drugs (ATDs) such as methimazole (MMI) and propylthiouracil (PTU)—carry their own risks, most notably teratogenicity and hepatotoxicity.
The most critical period for ATD-induced malformations is the first trimester, specifically during organogenesis (weeks 6–10). MMI is associated with a specific pattern of malformations known as MMI embryopathy (including aplasia cutis, choanal atresia, and esophageal atresia). While PTU is generally preferred in the first trimester due to a perceived lower risk of severe malformations, it is not without risk and has been linked to concerns regarding maternal hepatotoxicity. Consequently, international guidelines often recommend switching from MMI to PTU when planning pregnancy or upon the discovery of pregnancy in the early first trimester. The Danish PRETHYR (Pregnancy Investigations on Thyroid Disease) multicenter study was established to provide real-world evidence on how these complexities are managed in contemporary clinical practice.
Key Content: Evidence from the PRETHYR Multicenter Study
Study Design and Patient Population
The PRETHYR study is a landmark multicenter investigation in Denmark focusing on women with GD and those receiving ATD treatment during pregnancy. The first report from this cohort included 121 women, of whom 97.5% had a confirmed diagnosis of GD. The methodology involved a robust synthesis of patient questionnaires and detailed medical record reviews, capturing maternal characteristics and pre-conception biochemical markers, including thyroid-stimulating hormone (TSH), total triiodothyronine (TT3), and TSH-receptor antibodies (TRAb).
Among the study population, 102 women had a known history of thyroid disease prior to conception without having undergone definitive treatment (radioiodine or surgery). This specific subgroup provided the most critical data regarding current pharmacological management trends.
Patterns of Antithyroid Drug (ATD) Usage
Of the 102 women with pre-existing thyroid disease, 58.8% (n = 60) received ATDs during their pregnancy. The study highlighted several key management behaviors:
- Specialist Involvement: Women who were already being managed by an endocrinologist at the time of conception were significantly more likely to be treated with ATDs during pregnancy compared to those managed in primary care.
- Therapeutic Switching: Reflecting global safety recommendations, 59.1% of women treated with MMI prior to conception were switched to PTU. Interestingly, a small subset (10.7%) was switched from PTU to MMI, which may reflect individual clinical complexities or physician preference during different stages of the pregnancy.
- Timing and Duration: Treatment was predominantly concentrated in the first half of the first trimester. For many patients, ATDs were discontinued by the second or third trimester. This trend aligns with the known natural history of GD in pregnancy, where the induction of immune tolerance often leads to a spontaneous improvement in hyperthyroidism after the first trimester.
Biochemical Predictors of Treatment
The study found that biochemical profiles at the time of conception were strong predictors of whether a woman would require ATD therapy. Women who received ATDs had significantly:
- Lower preconception TSH levels.
- Higher total T3 (TT3) levels.
- Higher TSH-receptor antibody (TRAb) titers.
These findings reinforce the utility of pre-conception screening as a means of identifying women at the highest risk for requiring ongoing pharmacological support during the vulnerable first trimester.
Expert Commentary: Clinical Implications and Guidelines
Synthesis with International Standards
The PRETHYR study results demonstrate that Danish clinical practice largely adheres to the American Thyroid Association (ATA) and European Thyroid Association (ETA) guidelines. The high rate of MMI-to-PTU switching (nearly 60%) indicates a proactive approach to mitigating the risk of MMI embryopathy. However, the study also reveals the variability in clinical decision-making. The fact that approximately 40% of women with pre-existing disease did not require ATDs during pregnancy suggests that many cases of GD can be managed with close observation, particularly if the disease is in biochemical remission prior to conception.
Mechanistic Insights into Treatment Discontinuation
The discontinuation of ATDs by the second or third trimester observed in the PRETHYR cohort is biologically justified by the shift in maternal immunology. Pregnancy induces a shift toward a Th2-mediated immune environment and an increase in regulatory T cells, which typically reduces the titer of stimulatory TRAb. Clinicians can often leverage this physiological remission to withdraw ATDs, thereby eliminating further fetal exposure to the drugs during the later stages of development.
Limitations and Research Gaps
While the PRETHYR report offers valuable insights into the “what” and “how” of current treatment, it also points to areas where more data are needed. The relatively small sample size (121 women) in this first report limits the ability to perform detailed subgroup analyses on rare side effects or specific fetal outcomes. Future reports from the PRETHYR study are expected to correlate these treatment patterns with long-term neonatal health and developmental data, which remains a critical unmet need in obstetric endocrinology.
Conclusion
The first report from the Danish PRETHYR multicenter study confirms that the management of hyperthyroidism in pregnancy is heavily influenced by pre-conception specialist care and biochemical markers. The study underscores a high adherence to safety-first protocols, specifically the switching of ATDs and the early discontinuation of therapy whenever possible. For clinicians, these findings emphasize the importance of pre-pregnancy counseling and the aggressive monitoring of TRAb and thyroid hormones to optimize maternal and fetal safety. As real-world evidence continues to accumulate, the goal remains a personalized approach that minimizes drug exposure while maintaining strict euthyroidism.
References
- Uldall-Torp NM, Pedersen IB, Carlé A, et al. Antithyroid drug treatment in pregnancy: A first report from the Danish PRETHYR multicenter study. The Journal of clinical endocrinology and metabolism. 2026-03-06. PMID: 41790746.
- Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017;27(3):315-389. PMID: 28056690.
- Andersen SL, Olsen J, Laurberg P. Antithyroid Drug Side Effects in the Population and in Pregnancy of Denmark. J Clin Endocrinol Metab. 2016;101(4):1606-1614. PMID: 26863435.