Defining gestational thyroid dysfunction through modified non-pregnancy reference intervals: an individual participant meta-analysis

Joris A J Osinga; Scott M Nelson; John P Walsh; Ghalia Ashoor; Glenn E Palomaki; Abel López-Bermejo; Judit Bassols; Ashraf Aminorroaya; Maarten A C Broeren; Liangmiao Chen; Xuemian Lu; Suzanne J Brown; Flora Veltri; Kun Huang; Tuija Männistö; Marina Vafeiadi; Peter N Taylor; Fang-Biao Tao; Lida Chatzi; Maryam Kianpour; Eila Suvanto; Elena N Grineva; Kypros H Nicolaides; Mary E D'Alton; Kris G Poppe; Erik Alexander; Ulla Feldt-Rasmussen; Sofie Bliddal; Polina V Popova; Layal Chaker; W Edward Visser; Robin P Peeters; Arash Derakhshan; Tanja G M Vrijkotte; Victor J M Pop; Tim I M Korevaar

doi:10.1210/clinem/dgae528

Defining gestational thyroid dysfunction through modified non-pregnancy reference intervals: an individual participant meta-analysis

J Clin Endocrinol Metab. 2024 Jul 31:dgae528. doi: 10.1210/clinem/dgae528. Online ahead of print.

Authors

Joris A J Osinga^{1

2}, Scott M Nelson³, John P Walsh^{4

5}, Ghalia Ashoor⁶, Glenn E Palomaki⁷, Abel López-Bermejo^{8

9}, Judit Bassols¹⁰, Ashraf Aminorroaya¹¹, Maarten A C Broeren¹², Liangmiao Chen¹³, Xuemian Lu¹³, Suzanne J Brown⁴, Flora Veltri¹⁴, Kun Huang¹⁵, Tuija Männistö¹⁶, Marina Vafeiadi¹⁷, Peter N Taylor¹⁸, Fang-Biao Tao¹⁵, Lida Chatzi¹⁹, Maryam Kianpour¹¹, Eila Suvanto²⁰, Elena N Grineva²¹, Kypros H Nicolaides²², Mary E D'Alton²³, Kris G Poppe¹⁴, Erik Alexander²⁴, Ulla Feldt-Rasmussen²⁵, Sofie Bliddal²⁵, Polina V Popova²¹, Layal Chaker^{1

2

26}, W Edward Visser^{1

2}, Robin P Peeters^{1

2}, Arash Derakhshan^{1

2}, Tanja G M Vrijkotte²⁷, Victor J M Pop²⁸, Tim I M Korevaar^{1

2}

Affiliations

¹ Department of Internal Medicine, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
² Academic Center for Thyroid Diseases, Erasmus University Medical Center, 3000 CA, Rotterdam, the Netherlands.
³ School of Medicine, Dentistry and Nursing, University of Glasgow, G12 8QQ Glasgow, UK.
⁴ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands 6009, Western Australia, Australia.
⁵ Medical School, University of Western Australia, Crawley 6009, Western Australia, Australia.
⁶ Harris Birthright Research Center for Fetal Medicine, King's College Hospital, SE5 9RS London, United Kingdom.
⁷ Department of Pathology and Laboratory Medicine, Women & Infants Hospital and Alpert Medical School at Brown University, RI 02903 Providence, Rhode Island.
⁸ Pediatric Endocrinology Research Group, Girona Biomedical Research Institute (IDIBGI), Dr. Josep Trueta Hospital, 17007 Girona, Spain.
⁹ Departament de Ciències Mèdiques. Universitat de Girona, 17003, Girona, Spain.
¹⁰ Maternal-Fetal Metabolic Research Group, Girona Biomedical Research Institute (IDIBGI), Dr. Josep Trueta Hospital, 17007 Girona, Spain.
¹¹ Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, 81745-33871 Isfahan, Iran.
¹² Laboratory of Clinical Chemistry and Haematology, Máxima Medical Centre, 5504 DB Veldhoven, Netherlands.
¹³ Department of Endocrinology and Rui'an Center of the Chinese-American Research Institute for Diabetic Complications, Third Affiliated Hospital of Wenzhou Medical University, 325035 Wenzhou, China.
¹⁴ Endocrine Unit, Centre Hospitalier Universitaire Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium.
¹⁵ Department of Maternal, Child and Adolescent Health, Scientific Research Center in Preventive Medicine; School of Public Health; Anhui Medical University, 230032 Anhui, China.
¹⁶ NordLab, Oulu and Translational Medicine Research Unit, University of Oulu, 90570 Oulu, Finland.
¹⁷ Department of Social Medicine, School of Medicine, University of Crete, 710 03 Heraklion, Crete, Greece.
¹⁸ Thyroid Research Group, Systems Immunity Research Institute, Cardiff University School of Medicine, CF10 3EU Cardiff, UK.
¹⁹ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 90089 CA, USA.
²⁰ Department of Obstetrics and Gynecology and Medical Research Center Oulu, University of Oulu, 90570 Oulu, Finland.
²¹ Institute of Endocrinology, Almazov National Medical Research Centre, 197341 Saint Petersburg, Russia.
²² Department of Women and Children's Health, Faculty of Life Sciences and Medicine King's College London, SE5 9RS London, United Kingdom.
²³ Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, NY 10032 New York, USA.
²⁴ Division of Endocrinology, Hypertension and Diabetes, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115 MA, USA.
²⁵ Department of Medical Endocrinology and Metabolism, Copenhagen University Hospital, Rigshospitalet, and Department od Clinical Medicine, Faculty of Health and clinical Sciences, Copenhagen University, 2100 Copenhagen, Denmark.
²⁶ Department of Epidemiology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
²⁷ Department of Public and Occupational Health, Amsterdam UMC, University of Amsterdam, Amsterdam Public Health Research Institute, 1081 HV Amsterdam, the Netherlands.
²⁸ Department of Medical and Clinical Psychology, Tilburg University, 5000 LE Tilburg, The Netherlands.

PMID: 39083675
DOI: 10.1210/clinem/dgae528

Abstract

Background: Establishing local trimester-specific reference intervals for gestational TSH and FT4 is often not feasible, necessitating alternative strategies. We aimed to systematically quantify the diagnostic performance of standardized modifications of center-specific non-pregnancy reference intervals as compared to trimester-specific reference intervals.

Methods: We included prospective cohorts participating in the Consortium on Thyroid and Pregnancy. After relevant exclusions, reference intervals were calculated per cohort in thyroperoxidase antibody-negative women. Modifications to the non-pregnancy reference intervals included an absolute modification (per 0.1 mU/L TSH or 1 pmol/L FT4), relative modification (in steps of 5%) and fixed limits (upper TSH limit between 3.0 to 4.5 mU/L and lower FT4 limit 5-15 pmol/L). We compared (sub)clinical hypothyroidism prevalence, sensitivity and positive predictive value (PPV) of aforementioned methodologies with population-based trimester-specific reference intervals.

Results: The final study population comprised 52,496 participants in 18 cohorts. Optimal modifications of standard reference intervals to diagnose gestational overt hypothyroidism were -5% for the upper limit of TSH and +5% for the lower limit of FT4 (sensitivity 0.70, confidence interval [CI] 0.47-0.86; PPV 0.64, CI 0.54-0.74). For subclinical hypothyroidism, these were -20% for the upper limit of TSH and -15% for the lower limit of FT4 (sensitivity 0.91, CI 0.67-0.98; PPV 0.71, CI 0.58-0.80). Absolute and fixed modifications yielded similar results. Confidence intervals were wide, limiting generalizability.

Conclusion: We could not identify modifications of non-pregnancy TSH and FT4 reference intervals that would enable centers to adequately approximate trimester-specific reference intervals. Future efforts should be turned towards studying the meaningfulness of trimester-specific reference intervals and risk-based decision limits.

Keywords: Pregnancy; Reference values; Thyroid Function Tests; Thyroid Gland; Thyrotropin; Thyroxine.