Association of maternal prenatal copper concentration with gestational duration and preterm birth: a multi-country meta-analysis
Authors: Monangi Nagendra K. , Xu Huan , Fan Yuemei , Khanam Rasheda , Khan Waqasuddin , Deb Saikat , Pervin Jesmin , Price Joan T. , Kaur Lovejeet ,   INTERBIO-21st Study Consortium, Mahmud Abdullah Al , Thanh Le Quang , Care Angharad , Landero Julio A. , Combs Gerald F. , Belling Elizabeth , Chappell Joanne , Chen Jing , Kong Fansheng , Lacher Craig , Ahmed Salahuddin , Chowdhury Nabidul Haque , Rahman Sayedur , Kabir Furqan , Nisar Imran , Hotwani Aneeta , Mehmood Usma , Nizar Ambreen , Khalid Javairia , Dhingra Usha , Dutta Arup , Ali Said Mohamed , Aftab Fahad , Juma Mohammed Hamad , Rahman Monjur , Ahmed Tahmeed , Islam M Munirul , Vwalika Bellington , Musonda Patrick , Ashorn Ulla , Maleta Kenneth , Hallman Mikko , Goodfellow Laura , Gupta Juhi K. , Alfirevic Ana , Murphy Susan K. , Rand Larry , Ryckman Kelli K. , Murray Jeffrey C. , Bahl Rajiv , Litch James A. , Baruch-Gravett Courtney , Sopory Shailaja , Mouli Natchu Uma Chandra , Kumar Pavitra V , Kumari Neha , Thiruvengadam Ramachandran , Singh Atul Kumar , Kumar Pankaj , Alfirevic Zarko , Baqui Abdullah H. , Bhatnagar Shinjini , Hirst Jane E. , Hoyo Cathrine , Jehan Fyezah , Jelliffe-Pawlowski Laura , Rahman Anisur , Roth Daniel E. , Sazawal Sunil , Stringer Jeffrey S. A. , Ashorn Per , Zhang Ge , Muglia Louis J. 
Published: September 2022

Background

Copper (Cu), an essential trace mineral regulating multiple actions of inflammation and oxidative stress, has been implicated in risk for preterm birth (PTB). We aimed to determine the association of maternal plasma/serum Cu concentrations during pregnancy with PTB risk and gestational duration in a large multi-cohort study including diverse populations.

Methods

Gestational duration data and maternal plasma or serum samples of 10,449 singleton live births were obtained from 18 geographically diverse study cohorts. Maternal plasma or serum Cu concentrations were determined by inductively coupled plasma mass spectrometry (ICP-MS) analysis. The associations of maternal Cu with PTB and gestational duration were analyzed using logistic and linear regressions for each cohort. The estimates were then combined using meta-analysis. Associations between maternal Cu and acute phase reactants (APRs), malaria, and HIV infection were analyzed in 1239 samples from the Malawi cohort.

Findings

The maternal prenatal Cu concentration in our study samples followed a normal distribution with a mean of 1.92 μg/ml and a standard deviation of 0.43 μg/ml, and Cu concentrations increased with gestational age up to 20 weeks. The random effect meta-analysis across the 18 cohorts revealed that 1 μg/ml increase in maternal Cu concentration before the third trimester was associated with a higher risk of PTB with an OR of 1.30 (95% CI: 1.08 to 1.57) and shorter gestational duration of 1.64 days (95% CI: 0.56 to 2.73). The estimated effects were generally consistent across all sites. In the Malawi cohort, higher maternal Cu concentration, concentrations of multiple APRs and infections (malaria and HIV) were correlated and associated with greater risk of PTB and shorter gestational duration.

Interpretation

Our study supports a robust negative association between maternal mid-gestation Cu concentration and gestational duration and a positive association with risk for preterm birth. Cu concentration was strongly correlated with APRs and infection status suggesting its potential role in inflammation, a pathway implicated in the mechanisms of PTB. Therefore, maternal Cu could be used as a potential marker of the integrated inflammatory pathways during pregnancy and risk for preterm birth.