Meta-Analysis

. 2021 Sep;6(9):e005856.

doi: 10.1136/bmjgh-2021-005856.

Association of maternal prenatal selenium concentration and preterm birth: a multicountry meta-analysis

Nagendra Monangi^#^{1

2

3}, Huan Xu^#^{2

4}, Rasheda Khanam^#⁵, Waqasuddin Khan^#⁶, Saikat Deb^#^{7

8}, Jesmin Pervin^#⁹, Joan T Price^#¹⁰; INTERBIO-21st Study Consortium; Stephen H Kennedy¹¹, Abdullah Al Mahmud^#¹², Yuemei Fan^#¹³, Thanh Q Le^#¹⁴, Angharad Care^#¹⁵, Julio A Landero¹⁶, Gerald F Combs¹⁷, Elizabeth Belling⁴, Joanne Chappell^{2

4}, Fansheng Kong⁴, Criag Lacher¹⁸, Salahuddin Ahmed¹⁹, Nabidul Haque Chowdhury¹⁹, Sayedur Rahman¹⁹, Furqan Kabir⁶, Imran Nisar⁶, Aneeta Hotwani⁶, Usma Mehmood⁶, Ambreen Nizar⁶, Javairia Khalid⁶, Usha Dhingra⁷, Arup Dutta⁷, Said Ali⁸, Fahad Aftab⁸, Mohammed Hamad Juma⁸, Monjur Rahman²⁰, Bellington Vwalika²¹, Patrick Musonda²², Tahmeed Ahmed²³, Md Munirul Islam²⁴, Ulla Ashorn²⁵, Kenneth Maleta²⁶, Mikko Hallman²⁷, Laura Goodfellow²⁸, Juhi K Gupta²⁸, Ana Alfirevic²⁸, Susan Murphy²⁹, Larry Rand³⁰, Kelli K Ryckman³¹, Jeffrey C Murray³², Rajiv Bahl³³, James A Litch³⁴, Courtney Baruch-Gravett³⁴, Zarko Alfirevic^#³⁵, Per Ashorn^#^{36

37}, Abdullah Baqui^#³⁸, Jane Hirst^#³⁹, Cathrine Hoyo^#⁴⁰, Fyezah Jehan^#⁴¹, Laura L Jelliffe-Pawlowski^#⁴², Anisur Rahman^#⁹, Daniel E Roth^#⁴³, Sunil Sazawal^#^{7

8}, Jeffrey Stringer^#¹⁰, Ge Zhang^#^{44

3

4}, Louis Muglia^#^{2

3

4

45}

Affiliations

¹ Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA nagendra.monangi@cchmc.org Ge.Zhang@cchmc.org.
² Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center and March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, Ohio, USA.
³ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
⁴ Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
⁵ International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.
⁶ Biorepository and Omics Research Group, Department of Pediatrics and Child Health, Faculty of Health Sciences, Medical College, The Aga Khan University, Karachi, Sindh, Pakistan.
⁷ Center for Public Health Kinetics, New Delhi, India.
⁸ Research Division, Public Health Laboratory, Center for Public Health Kinetics, Chake Chake, Tanzania.
⁹ Maternal and Child Health Division, International Centre for Diarrhoeal Disease Research Bangladesh, Dhaka, Dhaka District, Bangladesh.
¹⁰ Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
¹¹ INTERBIO-21st Study Consortium, Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK.
¹² Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research Bangladesh, Dhaka, Dhaka District, Bangladesh.
¹³ Center for Child Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Pirkanmaa, Finland.
¹⁴ Benh Vien Tu Du, Ho Chi Minh City, Viet Nam.
¹⁵ Department of Women's and Children's Health, University of Liverpool, Liverpool, UK.
¹⁶ Department of Chemistry, University of Cincinnati, Cincinnati, Ohio, USA.
¹⁷ Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Medford, Massachusetts, USA.
¹⁸ Grand Forks Human Nutrition Research Center, USDA ARS, Grand Forks, North Dakota, USA.
¹⁹ Projahnmo Research Foundation, Dhaka, Bangladesh.
²⁰ Nutritional and Clinical Services Division, International Centre for Diarrhoeal Disease Research Bangladesh, Dhaka, Dhaka District, Bangladesh.
²¹ School of Medicine, University of Zambia, Lusaka, Zambia.
²² School of Public Health, University of Zambia, Lusaka, Zambia.
²³ Cardiology, ICDDR,B, Dhaka, Bangladesh.
²⁴ Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research Bangladesh, Dhaka, Bangladesh.
²⁵ University of Tampere, Tampere, Pirkanmaa, Finland.
²⁶ School of Public Health, University of Malawi College of Medicine, Blantyre, Malawi.
²⁷ Medical Research Centre Oulu, PEDEGO Research Unit, University of Oulu, Oulu, Pohjois-Pohjanmaa, Finland.
²⁸ Department of Women's and Children's Health, University of Liverpool, Liverpool, Merseyside, UK.
²⁹ Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, USA.
³⁰ Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California, USA.
³¹ Department of Epidemiology, University of Iowa, Iowa City, Iowa, USA.
³² Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA.
³³ Department of Medicine, World Health Organization, Geneva, Switzerland.
³⁴ Global Alliance to Prevent Prematurity and Stillbirth, Lynnwood, Washington, USA.
³⁵ Division of Perinatal Medicine, University of Liverpool, Liverpool, UK.
³⁶ Center for Child Health Research, Faculty of Medicine and Health Technology, University of Tampere, Tampere, Pirkanmaa, Finland.
³⁷ Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
³⁸ International Center for Maternal and Newborn Health, Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.
³⁹ Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK.
⁴⁰ Department of Biological Sciences and Center for Human Health and the Enivironment, North Carolina State University, Raleigh, North Carolina, USA.
⁴¹ Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan.
⁴² Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA.
⁴³ Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁴⁴ Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center and March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, Ohio, USA nagendra.monangi@cchmc.org Ge.Zhang@cchmc.org.
⁴⁵ Burroughs Wellcome Fund, Research Triangle Park, North Carolina, USA.

^# Contributed equally.

PMID: 34518202
PMCID: PMC8438754
DOI: 10.1136/bmjgh-2021-005856

Meta-Analysis

Association of maternal prenatal selenium concentration and preterm birth: a multicountry meta-analysis

Nagendra Monangi et al. BMJ Glob Health. 2021 Sep.

. 2021 Sep;6(9):e005856.

doi: 10.1136/bmjgh-2021-005856.

Authors

Affiliations

¹ Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA nagendra.monangi@cchmc.org Ge.Zhang@cchmc.org.
² Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center and March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, Ohio, USA.
³ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
⁴ Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
⁵ International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.
⁶ Biorepository and Omics Research Group, Department of Pediatrics and Child Health, Faculty of Health Sciences, Medical College, The Aga Khan University, Karachi, Sindh, Pakistan.
⁷ Center for Public Health Kinetics, New Delhi, India.
⁸ Research Division, Public Health Laboratory, Center for Public Health Kinetics, Chake Chake, Tanzania.
⁹ Maternal and Child Health Division, International Centre for Diarrhoeal Disease Research Bangladesh, Dhaka, Dhaka District, Bangladesh.
¹⁰ Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
¹¹ INTERBIO-21st Study Consortium, Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK.
¹² Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research Bangladesh, Dhaka, Dhaka District, Bangladesh.
¹³ Center for Child Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Pirkanmaa, Finland.
¹⁴ Benh Vien Tu Du, Ho Chi Minh City, Viet Nam.
¹⁵ Department of Women's and Children's Health, University of Liverpool, Liverpool, UK.
¹⁶ Department of Chemistry, University of Cincinnati, Cincinnati, Ohio, USA.
¹⁷ Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Medford, Massachusetts, USA.
¹⁸ Grand Forks Human Nutrition Research Center, USDA ARS, Grand Forks, North Dakota, USA.
¹⁹ Projahnmo Research Foundation, Dhaka, Bangladesh.
²⁰ Nutritional and Clinical Services Division, International Centre for Diarrhoeal Disease Research Bangladesh, Dhaka, Dhaka District, Bangladesh.
²¹ School of Medicine, University of Zambia, Lusaka, Zambia.
²² School of Public Health, University of Zambia, Lusaka, Zambia.
²³ Cardiology, ICDDR,B, Dhaka, Bangladesh.
²⁴ Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research Bangladesh, Dhaka, Bangladesh.
²⁵ University of Tampere, Tampere, Pirkanmaa, Finland.
²⁶ School of Public Health, University of Malawi College of Medicine, Blantyre, Malawi.
²⁷ Medical Research Centre Oulu, PEDEGO Research Unit, University of Oulu, Oulu, Pohjois-Pohjanmaa, Finland.
²⁸ Department of Women's and Children's Health, University of Liverpool, Liverpool, Merseyside, UK.
²⁹ Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, USA.
³⁰ Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California, USA.
³¹ Department of Epidemiology, University of Iowa, Iowa City, Iowa, USA.
³² Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA.
³³ Department of Medicine, World Health Organization, Geneva, Switzerland.
³⁴ Global Alliance to Prevent Prematurity and Stillbirth, Lynnwood, Washington, USA.
³⁵ Division of Perinatal Medicine, University of Liverpool, Liverpool, UK.
³⁶ Center for Child Health Research, Faculty of Medicine and Health Technology, University of Tampere, Tampere, Pirkanmaa, Finland.
³⁷ Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
³⁸ International Center for Maternal and Newborn Health, Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.
³⁹ Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK.
⁴⁰ Department of Biological Sciences and Center for Human Health and the Enivironment, North Carolina State University, Raleigh, North Carolina, USA.
⁴¹ Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan.
⁴² Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA.
⁴³ Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁴⁴ Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center and March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, Ohio, USA nagendra.monangi@cchmc.org Ge.Zhang@cchmc.org.
⁴⁵ Burroughs Wellcome Fund, Research Triangle Park, North Carolina, USA.

^# Contributed equally.

PMID: 34518202
PMCID: PMC8438754
DOI: 10.1136/bmjgh-2021-005856

Abstract

Background: Selenium (Se), an essential trace mineral, has been implicated in preterm birth (PTB). We aimed to determine the association of maternal Se concentrations during pregnancy with PTB risk and gestational duration in a large number of samples collected from diverse populations.

Methods: Gestational duration data and maternal plasma or serum samples of 9946 singleton live births were obtained from 17 geographically diverse study cohorts. Maternal Se concentrations were determined by inductively coupled plasma mass spectrometry analysis. The associations between maternal Se with PTB and gestational duration were analysed using logistic and linear regressions. The results were then combined using fixed-effect and random-effect meta-analysis.

Findings: In all study samples, the Se concentrations followed a normal distribution with a mean of 93.8 ng/mL (SD: 28.5 ng/mL) but varied substantially across different sites. The fixed-effect meta-analysis across the 17 cohorts showed that Se was significantly associated with PTB and gestational duration with effect size estimates of an OR=0.95 (95% CI: 0.9 to 1.00) for PTB and 0.66 days (95% CI: 0.38 to 0.94) longer gestation per 15 ng/mL increase in Se concentration. However, there was a substantial heterogeneity among study cohorts and the random-effect meta-analysis did not achieve statistical significance. The largest effect sizes were observed in UK (Liverpool) cohort, and most significant associations were observed in samples from Malawi.

Interpretation: While our study observed statistically significant associations between maternal Se concentration and PTB at some sites, this did not generalise across the entire cohort. Whether population-specific factors explain the heterogeneity of our findings warrants further investigation. Further evidence is needed to understand the biologic pathways, clinical efficacy and safety, before changes to antenatal nutritional recommendations for Se supplementation are considered.

Keywords: child health; environmental health; epidemiology; maternal health; nutrition.

PubMed Disclaimer

Conflict of interest statement

Competing interests: None declared.

Figures

**Figure 1**
Geographic location of study sites.

**Figure 2**
Flow chart of the study illustrating the total number of subjects, inclusion/exclusion criteria.

**Figure 3**
Selenium concentration by participating sites.

**Figure 4**
Meta-analysis of the association of maternal Se concentration with PTB (A) and gestational duration (B). (A) The estimated association between Se concentration and PTB is shown as OR per 15 ng/mL increase in Se concentration. (B) The estimated association between Se concentration and gestational duration is shown as change in gestational days per 15 ng/mL increase in Se concentration. PTB, preterm birth; Se, selenium.

**Figure 5**
Geographic distribution of the four Malawi subsites (A) and distributions of gestational duration and maternal Se concentration at these four sample recruitment sites (B). PTB, preterm birth; Se, selenium.

**Figure 6**
Selenium concentrations of Liverpool cohort (A) and the meta-analysis of maternal Se concentration associated with gestational duration (B). Se, selenium.

See this image and copyright information in PMC

References

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Association of maternal prenatal selenium concentration and preterm birth: a multicountry meta-analysis

Affiliations

Association of maternal prenatal selenium concentration and preterm birth: a multicountry meta-analysis

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Conflict of interest statement

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