Maternal Multiple Micronutrient Supplementation Stabilizes Mitochondrial DNA Copy Number in Pregnant Women in Lombok, Indonesia

Abstract

Background The Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) in Lombok, Indonesia showed that maternal multiple micronutrients (MMN), as compared with iron and folic acid (IFA), reduced fetal loss, early infant mortality, and low birth weight. Mitochondria play a key role during pregnancy by providing maternal metabolic energy for fetal development, but the effects of maternal supplementation during pregnancy on mitochondria are not fully understood. Objective The aim of this study was to assess the impact of MMN supplementation on maternal mitochondrial DNA copy number (mtDNA-CN). Methods We used archived venous blood specimens from pregnant women enrolled in the SUMMIT study. SUMMIT was a cluster-randomized double-blind controlled trial in which midwives were randomly assigned to distribute MMN or IFA to pregnant women. In this study, we selected 108 sets of paired baseline and postsupplementation samples (MMN = 54 and IFA = 54). Maternal mtDNA-CN was determined by real-time quantitative polymerase chain reaction in baseline and postsupplementation specimens. The association between supplementation type and change in mtDNA-CN was performed using rank-based estimation for linear models. Results In both groups, maternal mtDNA-CN at postsupplementation was significantly elevated compared with baseline (P < 0.001). The regression revealed that the MMN group had lower postsupplementation mtDNA-CN than the IFA group (β = −4.63, P = 0.003), especially for women with mtDNA-CN levels above the median at baseline (β = −7.49, P = 0.007). This effect was rapid, and observed within 33 d of initiation of supplementation (β = −7.39, P = 0.017). Conclusion Maternal MMN supplementation rapidly stabilized mtDNA-CN in pregnant women who participated in SUMMIT, indicating improved mitochondrial efficiency. The data provide a mechanistic basis for the beneficial effects of MMN on fetal growth and survival, and support the transition from routine IFA to MMN supplementation. This trial was registered at www.isrctn.com as ISRCTN34151616.

Nutrients, Mitochondrial Function, and Perinatal Health

“…Mitochondria are independent organelles which meet the energy requirement of the cell by producing adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS) [ 7 , 8 , 9 ]. Mitochondria have their own DNA (mtDNA), which encodes for many of the essential components of the OXPHOS chain, and, thus, is crucial to ATP generation [ 10 , 11 ].…”

“…Mitochondria seem to play a critical role in the physiological adaptations experienced during pregnancy. Their dynamic nature is crucial in modulating central cellular activities, turning into the main source of maternal metabolic energy for fetal development and matching the embryo’s changing energy requirements [ 6 , 7 ]. Additionally, they regulate processes such as folliculogenesis, oocyte maturation, corpus luteum and uterine function, embryogenesis, embryonic implantation, and fetoplacental development, through ROS signaling at physiological levels [ 8 ].…”

“…Mitochondria are the most abundant organelle in the oocyte and experience substantial structural and positional changes during preimplantation development [ 6 ]. As the main energy powerhouse, mitochondria are critical to maternal metabolism, on which fetal growth and development depend [ 6 , 7 ]. The objective of this work is to review the role of macronutrients and micronutrients on mitochondrial function and its influence on maternal and infant health.…”

Review of the evidence regarding the use of antenatal multiple micronutrient supplementation in low‐ and middle‐income countries

“…Throughout gestation iron, folate, zinc, niacin, and vitamins B 6 and A support the organogenesis and development of the fetal central nervous system, while iodine is important in early brain development . A recent study demonstrated that mitochondrial efficiency was greater for women receiving MMS compared with IFA . Thus, micronutrient deficiencies can result in a wide variety of birth defects and adverse pregnancy outcomes, including LBW, which is caused by either intrauterine growth restriction (IUGR) or preterm birth.…”

“…8,9 A recent study demonstrated that mitochondrial efficiency was greater for women receiving MMS compared with IFA. 65 Thus, micronutrient deficiencies can result in a wide variety of birth defects and adverse pregnancy outcomes, including LBW, which is caused by either intrauterine growth restriction (IUGR) or preterm birth.…”