Pre-eclampsia, soluble fms-like tyrosine kinase 1, and the risk of reduced thyroid function: nested case-control and population based studyBMJ 2009; 339 doi: https://doi.org/10.1136/bmj.b4336 (Published 18 November 2009) Cite this as: BMJ 2009;339:b4336
- Richard J Levine, senior investigator1,
- Lars J Vatten, professor2,
- Gary L Horowitz, associate professor3,
- Cong Qian, statistician4,
- Pal R Romundstad, associate professor2,
- Kai F Yu, senior statistician1,
- Anthony N Hollenberg, associate professor5,
- Alf I Hellevik, medical student2,
- Bjorn O Asvold, postdoctoral fellow2,
- S Ananth Karumanchi, associate professor567
- 1Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Division of Epidemiology, Statistics, and Prevention Research, Bethesda, MD 20892, USA
- 2Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- 3Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
- 4Glotech, Rockville, MD, USA
- 5Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
- 6Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
- 7Howard Hughes Medical Institute, Boston, MA, USA
- Correspondence to: R J Levine or S A Karumanchi
- Accepted 29 June 2009
Objective To determine if pre-eclampsia is associated with reduced thyroid function during and after pregnancy.
Design Nested case-control study during pregnancy and population based follow-up study after pregnancy.
Setting Calcium for Pre-eclampsia Prevention trial of healthy pregnant nulliparous women in the United States during 1992-5, and a Norwegian population based study (Nord-Trondelag Health Study or HUNT-2) during 1995-7 with linkage to the medical birth registry of Norway.
Participants All 141 women (cases) in the Calcium for Pre-eclampsia Prevention trial with serum measurements before 21 weeks’ gestation (baseline) and after onset of pre-eclampsia (before delivery), 141 normotensive controls with serum measurements at similar gestational ages, and 7121 women in the Nord-Trondelag Health Study whose first birth had occurred in 1967 or later and in whom serum levels of thyroid stimulating hormone had been subsequently measured.
Main outcome measures Thyroid function tests and human chorionic gonadotrophin and soluble fms-like tyrosine kinase 1 concentrations in the Calcium for Pre-eclampsia Prevention cohort and odds ratios for levels of thyroid stimulating hormone above the reference range, according to pre-eclampsia status in singleton pregnancies before the Nord-Trondelag Health Study.
Results In predelivery specimens of the Calcium for Pre-eclampsia Prevention cohort after the onset of pre-eclampsia, thyroid stimulating hormone levels increased 2.42 times above baseline compared with a 1.48 times increase in controls. The ratio of the predelivery to baseline ratio of cases to that of the controls was 1.64 (95% confidence interval 1.29 to 2.08). Free triiodothyronine decreased more in the women with pre-eclampsia than in the controls (case ratio to control ratio 0.96, 95% confidence interval 0.92 to 0.99). The predelivery specimens but not baseline samples from women with pre-eclampsia were significantly more likely than those from controls to have concentrations of thyroid stimulating hormone above the reference range (adjusted odds ratio 2.2, 95% confidence interval 1.1 to 4.4). Both in women who developed pre-eclampsia and in normotensive controls the increase in thyroid stimulating hormone concentration between baseline and predelivery specimens was strongly associated with increasing quarters of predelivery soluble fms-like tyrosine kinase 1 (P for trend 0.002 and <0.001, respectively). In the Nord-Trondelag Health Study, women with a history of pre-eclampsia in their first pregnancy were more likely than other women (adjusted odds ratio 1.7, 95% confidence interval 1.1 to 2.5) to have concentrations of thyroid stimulating hormone above the reference range (>3.5 mIU/l). In particular, they were more likely to have high concentrations of thyroid stimulating hormone without thyroid peroxidase antibodies (adjusted odds ratio 2.6, 95% confidence interval 1.3 to 5.0), suggesting hypothyroid function in the absence of an autoimmune process. This association was especially strong (5.8, 1.3 to 25.5) if pre-eclampsia had occurred in both the first and the second pregnancies.
Conclusion Increased serum concentration of soluble fms-like tyrosine kinase 1 during pre-eclampsia is associated with subclinical hypothyroidism during pregnancy. Pre-eclampsia may also predispose to reduced thyroid function in later years.
We thank the CPEP (Calcium for Pre-eclampsia Prevention) Study Group who assembled the database and specimen repository used here: J C Hauth, R Goldenberg, and B S Stofan (University of Alabama at Birmingham), L B Curet, G M Joffe, and V Dorato (University of New Mexico at Albuquerque), B M Sibai, SA Friedman, B M Mercer, and T Carr (University of Tennessee at Memphis), P M Catalano, A S Petrulis, and L Barabach (Case Western Reserve University at MetroHealth Medical Center, Cleveland), C Morris, S-L Jacobson, and K McCracken (Oregon Health Sciences University, Portland), J R Esterlitz, M G Ewell, and D M Brown (EMMES, Rockville), R J Levine, R DerSimonian, J D Clemens, M A Klebanoff, E G Raymond, J G Rigau-Perez, and H Shifrin (the Eunice Kennedy Shriver National Institute of Child Health), and J A Cutler and D E Bild (the National Heart, Lung, and Blood Institute); M Lindheimer, C Begg, T Chalmers, M Druzin, R Sokol (data safety and monitoring board); the participants; Frank Epstein, Nisha Parikh, Alexander Holston, Evelyn Wang, Hannah Elson, and Maren May for helpful discussions; Patricia Moyer for assistance with figures; and the Nord-Trondelag Health Study for permission to use the combined data with the medical birth registry of Norway.
Contributors: SAK and RJL had the original idea for the study. GLH carried out the thyroid function tests and measured the human chorionic gonadotrophin in the specimens from the Calcium for Pre-eclampsia Prevention trial. RJL, CQ, KFY, and SAK analysed data from the Calcium for Pre-eclampsia Prevention trial, and LJV, PRR, AIH, and BOA analysed the data from the Nord-Trondelag Health Study. RJL, SAK, and LJV wrote the paper assisted by GLH, CQ, PRR, KFY, ANH, BOA, and AIH, who also helped interpret the results. RJL has access to the original data from the Calcium for Pre-eclampsia Prevention trial and is guarantor of the Calcium for Pre-eclampsia Prevention trial results. LJV has access to the original data from the Nord-Trondelag Health Study and is guarantor of the Nord-Trondelag Health Study results.
Funding: This study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contract N01-HD-5-3398) and by salary support from the intramural research programme of the National Institutes of Health. The Calcium for Pre-eclampsia Prevention trial was supported by the National Institute of Child Health and Human Development (contracts N01-HD-1-3121-3126, N01-HD-3154, and N01-HD-5-3246), with cofunding from the National Heart, Lung, and Blood Institute. SAK is supported by a clinical scientist award by the Burroughs Wellcome Fund and is an investigator of the Howard Hughes Medical Institute and an established investigator of the American Heart Association. The Nord-Trondelag Health Study is a collaborative effort of the Norwegian University of Science and Technology, the Norwegian Institute of Public Health, and the Nord-Trondelag County Council. This substudy of the Nord-Trondelag Health Study was supported by the Norwegian University of Science and Technology and by the Central Norway Regional Health Authority.
Competing interests: SAK has served as a consultant to Abbott, Beckman Coulter, Roche, and Johnson & Johnson and has been named coinventor on multiple provisional patents filed by Beth Israel Deaconess Medical Center for the use of angiogenesis related proteins for the diagnosis and treatment of pre-eclampsia. These patents have been non-exclusively licensed to several companies.
Ethical approval: Because the study used specimens that had been collected as part of the Calcium for Pre-eclampsia trial and could not be linked to identifiable women, the Office of Human Subjects Research of the National Institutes of Health granted an exemption from the requirement for review and approval by the institutional review board. Use of the Nord-Trondelag Health Study and Norwegian birth registry was approved by the Norwegian regional committee for medical research ethics and by the Norwegian Data Inspectorate.
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