Arash Derakhshan1, Robin P Peeters1, Peter N Taylor2, Sofie Bliddal3, David M Carty4, Margreet Meems5, Bijay Vaidya6, Liangmiao Chen7, Bridget A Knight8, Farkhanda Ghafoor9, Polina V Popova10, Lorena Mosso11, Emily Oken12, Eila Suvanto13, Aya Hisada14, Jun Yoshinaga15, Suzanne J Brown16, Judit Bassols17, Juha Auvinen18, Wichor M Bramer19, Abel López-Bermejo20, Colin M Dayan21, Robert French22, Laura Boucai23, Marina Vafeiadi24, Elena N Grineva10, Victor J M Pop5, Tanja G Vrijkotte25, Leda Chatzi26, Jordi Sunyer27, Ana Jiménez-Zabala28, Isolina Riaño29, Marisa Rebagliato30, Xuemian Lu7, Amna Pirzada31, Tuija Männistö32, Christian Delles33, Ulla Feldt-Rasmussen3, Erik K Alexander34, Scott M Nelson35, Layal Chaker36, Elizabeth N Pearce37, Mònica Guxens38, Eric A P Steegers39, John P Walsh40, Tim I M Korevaar41. 1. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands; Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, Netherlands. 2. Thyroid Research Group, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, UK. 3. Department of Medical Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 4. Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, Glasgow, UK; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK. 5. Department of Medical and Clinical Psychology, Tilburg University, Tilburg, Netherlands. 6. Department of Endocrinology, Royal Devon and Exeter Hospital National Health Service Foundation Trust, University of Exeter Medical School, Exeter, UK. 7. Department of Endocrinology, Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. 8. National Institute for Health Research Exeter Clinical Research Facility, Royal Devon and Exeter Hospital National Health Service Foundation Trust, University of Exeter Medical School, Exeter, UK. 9. National Health Research Complex, Shaikh Zayed Medical Complex, Lahore, Pakistan. 10. Almazov National Medical Research Centre, Saint Petersburg, Russia; Department of Faculty Therapy, St Petersburg Pavlov State Medical University, Saint Petersburg, Russia. 11. Department of Endocrinology, Pontificia Universidad Catolica de Chile, Santiago, Chile. 12. Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School, Boston, MA, USA; Harvard Pilgrim Health Care Institute, Boston, MA, USA; Department of Nutrition, Harvard T H Chan School of Public Health, Boston, MA, USA. 13. Department of Obstetrics and Gynecology, University of Oulu, Oulu, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland. 14. Center for Preventive Medical Sciences, Chiba University, Chiba, Japan. 15. Faculty of Life Sciences, Toyo University, Gunma, Japan. 16. Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia. 17. Maternal-Fetal Metabolic Research Group, Girona Biomedical Research Institute (IDIBGI), Dr Josep Trueta Hospital, Girona, Spain. 18. Center for Life Course Health Research, University of Oulu, Oulu, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland. 19. Medical Library, Erasmus University Medical Center, Rotterdam, Netherlands. 20. Pediatric Endocrinology Research Group, Girona Biomedical Research Institute (IDIBGI), Dr Josep Trueta Hospital, Girona, Spain. 21. Thyroid Research Group, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, UK. 22. School of Medicine, Cardiff University, Cardiff, UK; Centre for Multilevel Modelling, University of Bristol, Bristol, UK. 23. Department of Medicine, Division of Endocrinology, Memorial Sloan-Kettering Cancer Center, Weill Cornell University, New York, NY, USA. 24. Department of Social Medicine, University of Crete, Heraklion, Greece. 25. Department of Public Health, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, Netherlands. 26. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, CA, USA. 27. ISGlobal, Barcelona, Spain; Pompeu Fabra University, Barcelona, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. 28. Biodonostia Health Research Institute, San Sebastian, Spain; Public Health Division of Gipuzkoa, Basque Government, San Sebastian, Spain. 29. Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain; Department of Pediatrics, Hospital Universitario Central de Asturias (Oviedo), Spain. 30. Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain; School of Medicine, Universitat Jaume I, Castelló de la Plana, Spain. 31. Shifa College of Medicine, Islamabad, Pakistan. 32. Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland; Northern Finland Laboratory Center Nordlab, Oulu University Hospital and University of Oulu, Oulu, Finland. 33. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK. 34. Division of Endocrinology, Hypertension and Diabetes, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 35. School of Medicine, University of Glasgow, Glasgow, UK; National Institute for Health Research, Bristol Biomedical Research Centre, Bristol, UK. 36. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands; Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, Netherlands. 37. Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, MA, USA. 38. ISGlobal, Barcelona, Spain; Pompeu Fabra University, Barcelona, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain; Department of Child and Adolescent Psychiatry/ Psychology, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, Netherlands. 39. Department of Obstetrics and Gynaecology, Erasmus University Medical Center, Rotterdam, Netherlands. 40. Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia; Medical School, University of Western Australia, Crawley, WA, Australia. 41. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands; Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, Netherlands. Electronic address: t.korevaar@erasmusmc.nl.
Abstract
BACKGROUND: Adequate transplacental passage of maternal thyroid hormone is important for normal fetal growth and development. Maternal overt hypothyroidism and hyperthyroidism are associated with low birthweight, but important knowledge gaps remain regarding the effect of subclinical thyroid function test abnormalities on birthweight-both in general and during the late second and third trimester of pregnancy. The aim of this study was to examine associations of maternal thyroid function with birthweight. METHODS: In this systematic review and individual-participant data meta-analysis, we searched MEDLINE (Ovid), Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar from inception to Oct 15, 2019, for prospective cohort studies with data on maternal thyroid function during pregnancy and birthweight, and we issued open invitations to identify study authors to join the Consortium on Thyroid and Pregnancy. We excluded participants with multiple pregnancies, in-vitro fertilisation, pre-existing thyroid disease or thyroid medication usage, miscarriages, and stillbirths. The main outcomes assessed were small for gestational age (SGA) neonates, large for gestational age neonates, and newborn birthweight. We analysed individual-participant data using mixed-effects regression models adjusting for maternal age, BMI, ethnicity, smoking, parity, gestational age at blood sampling, fetal sex, and gestational age at birth. The study protocol was pre-registered at the International Prospective Register of Systematic Reviews, CRD42016043496. FINDINGS: We identified 2526 published reports, from which 36 cohorts met the inclusion criteria. The study authors for 15 of these cohorts agreed to participate, and five more unpublished datasets were added, giving a study population of 48 145 mother-child pairs after exclusions, of whom 1275 (3·1%) had subclinical hypothyroidism (increased thyroid stimulating hormone [TSH] with normal free thyroxine [FT4]) and 929 (2·2%) had isolated hypothyroxinaemia (decreased FT4 with normal TSH). Maternal subclinical hypothyroidism was associated with a higher risk of SGA than was euthyroidism (11·8% vs 10·0%; adjusted risk difference 2·43%, 95% CI 0·43 to 4·81; odds ratio [OR] 1·24, 1·04 to 1·48; p=0·015) and lower mean birthweight (mean difference -38 g, -61 to -15; p=0·0015), with a higher effect estimate for measurement in the third trimester than in the first or second. Isolated hypothyroxinaemia was associated with a lower risk of SGA than was euthyroidism (7·3% vs 10·0%, adjusted risk difference -2·91, -4·49 to -0·88; OR 0·70, 0·55 to 0·91; p=0·0073) and higher mean birthweight (mean difference 45 g, 18 to 73; p=0·0012). Each 1 SD increase in maternal TSH concentration was associated with a 6 g lower birthweight (-10 to -2; p=0·0030), with higher effect estimates in women who were thyroid peroxidase antibody positive than for women who were negative (pinteraction=0·10). Each 1 SD increase in FT4 concentration was associated with a 21 g lower birthweight (-25 to -17; p<0·0001), with a higher effect estimate for measurement in the third trimester than the first or second. INTERPRETATION: Maternal subclinical hypothyroidism in pregnancy is associated with a higher risk of SGA and lower birthweight, whereas isolated hypothyroxinaemia is associated with lower risk of SGA and higher birthweight. There was an inverse, dose-response association of maternal TSH and FT4 (even within the normal range) with birthweight. These results advance our understanding of the complex relationships between maternal thyroid function and fetal outcomes, and they should prompt careful consideration of potential risks and benefits of levothyroxine therapy during pregnancy. FUNDING: Netherlands Organization for Scientific Research (grant 401.16.020).
BACKGROUND: Adequate transplacental passage of maternal thyroid hormone is important for normal fetal growth and development. Maternal overt hypothyroidism and hyperthyroidism are associated with low birthweight, but important knowledge gaps remain regarding the effect of subclinical thyroid function test abnormalities on birthweight-both in general and during the late second and third trimester of pregnancy. The aim of this study was to examine associations of maternal thyroid function with birthweight. METHODS: In this systematic review and individual-participant data meta-analysis, we searched MEDLINE (Ovid), Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar from inception to Oct 15, 2019, for prospective cohort studies with data on maternal thyroid function during pregnancy and birthweight, and we issued open invitations to identify study authors to join the Consortium on Thyroid and Pregnancy. We excluded participants with multiple pregnancies, in-vitro fertilisation, pre-existing thyroid disease or thyroid medication usage, miscarriages, and stillbirths. The main outcomes assessed were small for gestational age (SGA) neonates, large for gestational age neonates, and newborn birthweight. We analysed individual-participant data using mixed-effects regression models adjusting for maternal age, BMI, ethnicity, smoking, parity, gestational age at blood sampling, fetal sex, and gestational age at birth. The study protocol was pre-registered at the International Prospective Register of Systematic Reviews, CRD42016043496. FINDINGS: We identified 2526 published reports, from which 36 cohorts met the inclusion criteria. The study authors for 15 of these cohorts agreed to participate, and five more unpublished datasets were added, giving a study population of 48 145 mother-child pairs after exclusions, of whom 1275 (3·1%) had subclinical hypothyroidism (increased thyroid stimulating hormone [TSH] with normal free thyroxine [FT4]) and 929 (2·2%) had isolated hypothyroxinaemia (decreased FT4 with normal TSH). Maternal subclinical hypothyroidism was associated with a higher risk of SGA than was euthyroidism (11·8% vs 10·0%; adjusted risk difference 2·43%, 95% CI 0·43 to 4·81; odds ratio [OR] 1·24, 1·04 to 1·48; p=0·015) and lower mean birthweight (mean difference -38 g, -61 to -15; p=0·0015), with a higher effect estimate for measurement in the third trimester than in the first or second. Isolated hypothyroxinaemia was associated with a lower risk of SGA than was euthyroidism (7·3% vs 10·0%, adjusted risk difference -2·91, -4·49 to -0·88; OR 0·70, 0·55 to 0·91; p=0·0073) and higher mean birthweight (mean difference 45 g, 18 to 73; p=0·0012). Each 1 SD increase in maternal TSH concentration was associated with a 6 g lower birthweight (-10 to -2; p=0·0030), with higher effect estimates in women who were thyroid peroxidase antibody positive than for women who were negative (pinteraction=0·10). Each 1 SD increase in FT4 concentration was associated with a 21 g lower birthweight (-25 to -17; p<0·0001), with a higher effect estimate for measurement in the third trimester than the first or second. INTERPRETATION: Maternal subclinical hypothyroidism in pregnancy is associated with a higher risk of SGA and lower birthweight, whereas isolated hypothyroxinaemia is associated with lower risk of SGA and higher birthweight. There was an inverse, dose-response association of maternal TSH and FT4 (even within the normal range) with birthweight. These results advance our understanding of the complex relationships between maternal thyroid function and fetal outcomes, and they should prompt careful consideration of potential risks and benefits of levothyroxine therapy during pregnancy. FUNDING: Netherlands Organization for Scientific Research (grant 401.16.020).
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